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Alcohol’s Burden on Immunity Following Burn, Hemorrhagic Shock, or Traumatic Brain Injury

Patricia E. Molina, M.D., Ph.D.; Paige S. Katz, Ph.D.; Flavia Souza-Smith, Ph.D.; Stephen M. Ford; Sophie X. Teng, Ph.D.; Tracy Y. Dodd, Ph.D.; John K. Maxi; and Jacques P. Mayeux, M.S.

Patricia E. Molina, M.D., Ph.D., is a professor and the department head; Paige S. Katz, Ph.D., is a postdoctoral fellow; Flavia Souza-Smith, Ph.D., is an instructor; Stephen M. Ford is a graduate student; Sophie X. Teng, Ph.D., is a medical student; Tracy Y. Dodd, Ph.D., is a postdoctoral fellow; John K. Maxi is a graduate student; Jacques P. Mayeux, M.S., is a graduate student; all in the Department of Physiology, Comprehensive Alcohol Research Center and Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Volume 37, Issue 2 ⦁ Pages: 263-278

    Abstract

    Alcohol consumption contributes to increased incidence and severity of traumatic injury. Compared with patients who do not consume alcohol, alcohol-consuming patients have higher rates of long-term morbidity and mortality during recovery from injury. This can be attributed in part to an impaired immune response in individuals who consume alcohol. Acute and chronic alcohol use can affect both the innate and adaptive immune defense responses within multiple organ systems; the combination of alcohol use and injury results in increased susceptibility to bacterial and viral pathogens. This review examines the major deleterious effects of alcohol on immunity following tissue damage or traumatic injury, with a focus on alcohol’s influence on the ability of the immune and major organ systems to fight disease and to repair damaged tissues following injury.

    The incidence of traumatic injury in alcohol-intoxicated individuals continues to escalate. According to the Centers for Disease Control and Prevention (2012a), more than 38 million American alcohol users consume 5 or more drinks on the same occasion (i.e., binge drink) and do so about 4 times per month. This behavior is highly conducive to unintentional or accidental traumatic injury, which according to the National Vital Statistics Reports is the leading cause of years of potential life lost (YPLL) before age 45. Unintentional injury causes more YPLL than that attributed to cancer, intentional injuries, heart disease, and HIV individually (Centers for Disease Control and Prevention 2009). Data from the National Center for Injury Prevention and Control, as well as data derived from prospective and retrospective studies, show that up to 40 percent of victims of traumatic injury have positive blood alcohol concentrations (BAC), with 35 percent presenting with blood alcohol levels above the legal limit of intoxication (Beech and Mercadel 1998).

    The severity of trauma, reduced blood flow and oxygen delivery (i.e., hemorrhagic shock, referred to as shock in this article), and tissue injury is greater in intoxicated victims than in sober victims, resulting in higher mortality rates in the alcohol-consuming patient population (Pories et al. 1992). Although immediate mortality from traumatic injury has improved significantly as a result of aggressive resuscitation, long-term morbidity and mortality continue to be unacceptably high during the recovery period. The prevalence of morbidity and mortality is particularly attributable to the altered immune response among impaired patients to subsequent challenges, such as surgery or infection, leading to multiple organ failure (Roumen et al. 1993; Sauaia et al. 1994). Acute alcohol intoxication complicates the initial management of trauma victims and is associated with greater incidences of pneumonia and respiratory distress, requiring ventilator assistance during hospitalization (Gurney et al. 1992; Jurkovich et al. 1992). In addition, major complications including tracheobronchitis, pneumonia, pancreatitis, and sepsis are significantly increased in patients with high levels of carbohydrate-deficient transferrin (CDT), a marker for alcoholism (Spies et al. 1998). European studies show that, compared with nonalcoholics, alcoholics more frequently develop major complications and require a significantly prolonged stay in the intensive care unit (ICU) following trauma (Spies et al. 1996a).

    Excessive acute and chronic alcohol consumption has significant effects at multiple cellular levels, affecting both innate and adaptive immune mechanisms (Molina et al. 2010). Both chronic and acute patterns of alcohol abuse lead to impaired immune responses, resulting in increased susceptibility to infectious diseases caused by bacterial and viral pathogens (Brown et al. 2006). Clinical and preclinical studies show that the combined effects of alcohol and injury result in greater immune disruption than either insult alone (Messingham et al. 2002). This article reviews the current understanding of the burden of alcohol on the immune response to three specific traumatic events: burn, shock, and traumatic brain injury (TBI). The major pathophysiological consequences of these injuries on other major organ systems— including the cardiovascular system, pulmonary system, and gastrointestinal tract—are highlighted with emphasis on the contribution of alcohol-induced immunomodulation to postinjury morbidity.

    Reestablishment of homeostasis after a traumatic insult involves activation of host defense mechanisms for self-protection against toxic inflammatory processes and tissue repair. Trauma victims frequently are subjected to necessary invasive procedures, such as surgery and anesthesia. In addition, trauma victims frequently are exposed to subsequent challenges, particularly infection. These additional stresses to an already compromised inflammatory and neuroendocrine milieu further contribute to morbidity and mortality in this patient population. Traumatic injury and hemorrhagic shock produce a temporal pattern with early upregulation of pro-inflammatory cytokine1 gene product expression and with later suppression of stimulated pro-inflammatory cytokine release (Hierholzer et al. 1998; Molina et al. 2001). Together, these alterations lead to generalized immunosuppression, ultimately resulting in an increased susceptibility to infection (Abraham 1993; Ertel et al. 1993).


    1 Cytokines are proteins involved in cell signaling. They are produced by a variety of cells including immune cells and regulate the immune response.

    Alcohol has been shown to affect multiple aspects of the host immune response, contributing to pathological processes (Szabo 1998). For example, alcohol alters the expression and processing of cytokines and a type of cytokine known as chemokines (D’Souza et al. 1989; Standiford and Danforth 1997), the expression of adhesion molecules (Zhang et al. 1999), inflammatory cell recruitment (Patel et al. 1996; Shellito and Olariu 1998) and accumulation, and oxidative capacity of macrophages (Nilsson and Palmblad 1988). The monocyte/macrophage production of cytokines and chemokines, in particular interleukin (IL)-8 and tumor necrosis factor-α (TNF-α), is critical in the regulation of the acute inflammatory host response to infectious challenge. The combined inhibition of pro- inflammatory cytokine production and neutrophil activation and migration to a site of infection has been suggested to contribute to the enhanced susceptibility to infection in alcoholic individuals (Nelson et al. 1991) and to the increased risk of trauma- and burn-related infections associated with alcohol intoxication (Arbabi et al. 1999). Several lines of evidence show that these alcohol-mediated alterations in host defense following injury lead to increased morbidity and mortality from infections during the recovery period (Faunce et al. 2003; Messingham et al. 2002; Zambell et al. 2004). In addition, considerable evidence suggests that the severity of disease processes is greater in intoxicated trauma victims than in nonintoxicated counterparts (Spies et al. 1996a,b, 1998). In particular, immunoparalysis characterized by inhibition of stimulated pro-inflammatory cytokine release (Angele et al. 1999) and alterations of both cellular and humoral immunity (Napolitano et al. 1995; Wichmann et al. 1998) have been identified as risk factors for infection and progression to organ injury during the posttraumatic injury period (Abraham 1993; Ertel et al. 1993).

    The systemic response to injury is associated with marked activation of neuroendocrine pathways that contribute to cardiovascular adaptation to blood loss, injury, and pain but also exert immunomodulatory effects (Molina 2005). Catecholamines (e.g., dopamine, norepinephrine, and epinephrine), and drugs that mimic their effects (i.e., adrenergic agonists), are especially known to exert important regulatory functions on macrophages as well as on B- and T-lymphocyte cytokine production, proliferation, and antibody secretion; dendritic cell function; cytokine and chemokine release; and nitric oxide (NO) production (Madden et al. 1995). The relevance of these control mechanisms and the implications of their dysregulation have been demonstrated by the high incidence of infection in patients who experience elevated temperature, increased heart rate, and perspiration (i.e., “sympathetic storm”) following acute brain trauma and myocardial infarction (Woiciechowsky et al. 1998). Alcohol intoxication produces marked disruption of several neuroendocrine pathways. Disruption of the homeostatic neuroendocrine counterregulatory response to shock impairs hemodynamic stability and recovery, contributing to compromised blood flow and increased end-organ injury (Molina et al. 2013). Specifically, binge alcohol use blunts central neuroendocrine and autonomic activation, and this seems to result from alcohol-accentuated NO production in the periventricular nucleus (PVN) of the hypothalamus (Whitaker et al. 2010). Alcohol-mediated impairment of neuroendocrine counterregulatory responses to traumatic injury not only exacerbates low blood pressure (i.e., hypotension) during hemorrhage but also attenuates blood pressure recovery during fluid resuscitation, leading to significant alterations in blood flow redistribution and notably affecting circulation in the gastrointestinal tract (Wang et al. 1993). Studies have shown that alcohol-intoxicated animals have greater reduction of blood flow to the liver, kidney, and small and large intestines than nonintoxicated animals, following shock and fluid resuscitation (Sulzer et al. 2013). These macro- and microcirculatory changes during trauma and hemorrhage have been implicated in the subsequent development of sepsis and multiple organ failure (Peitzman et al. 1995) and contribute to an increased host susceptibility to infection and tissue injury during recovery (Mathis et al. 2006; Xu et al. 2002). People who abuse alcohol, including both binge and chronic drinkers, have a higher incidence of traumatic injury such as burn, shock, and TBI. The host response to these diverse insults is markedly affected by both patterns of alcohol abuse and some systems—including gastrointestinal, cardiovascular, and pulmonary—are more affected than others according to the specific injury.

    Alcohol and Burn Injury

    Burn injury is a common type of traumatic injury that affects thousands of people in the United States every year (Bessey et al. 2014). Approximately 50 percent of burn-injured patients have detectable blood alcohol levels at the time of hospital admission (Haum et al. 1995; McGwin et al. 2000), and these patients have more complications, require longer hospital stays, and have greater mortality rates than those with a similar degree of injury who are not intoxicated at the time of injury (McGill et al. 1995). Most morbidity and mortality among patients who survive initial injury is attributed to complications stemming from infection (Baker et al. 1980). Therefore, the pre-burn immunological condition of injured patients affects susceptibility to infection and survival. Several mechanisms contribute to infection in burn patients, including loss of barrier function, changes in normal flora, wound ischemia, and cellular immunosuppression resulting from pro-inflammatory processes. Neutrophil, helper T-cell, and macrophage dysfunction; increased pro-inflammatory cytokine production; and enhanced production of immunosuppressive factors have all been shown to contribute to the pathophysiological response to burn injury (Faunce et al. 1998; Messingham et al. 2000). The mechanisms that contribute to infection in burn patients are influenced by acute and chronic alcohol intoxication and will be discussed below (see figure 1).

    Image
    Salient gastrointestinal, pulmonary, and metabolic pathophysiological consequences of alcohol abuse prior to, or at the time of, burn injury.
    Figure 1 Salient gastrointestinal, pulmonary, and metabolic pathophysiological consequences of alcohol abuse prior to, or at the time of, burn injury. The decrease in gut barrier function leads to increased permeability and bacterial translocation that enhances the risk for bacterial infections and lung injury. Marked alterations in metabolic responses, characterized by altered adipokine profile consistent with increased insulin resistance, collectively contribute to greater morbidity and mortality post–burn injury.

    Research by Kovacs and colleagues (2008) has offered insight into the combined effects of`burn injury and alcohol intoxication on immunity (Bird and Kovacs 2008). Chronic alcohol abuse alone increases the risk for lung infection (Baker and Jerrells 1993), impairs the phagocytic activity of alveolar macrophages and clearance of infectious particles from the airways, and impairs oxidant radicals, chemokine, and cytokine release that are required for microbial killing (Brown et al. 2007; Mehta and Guidot 2012; Molina et al. 2010). Acute alcohol intoxication prior to burn injury significantly suppresses the immune response relative to the insult alone (Faunce et al. 1997) and causes greater suppression of T-cell proliferation and response, reduced IL-2 production, and increased IL-6 production and circulating levels (Choudhry et al. 2000; Faunce et al. 1998). The T-cell and cytokine impairment caused by the combined effect of alcohol and burn injury may further suppress cell-mediated immunity, resulting in even greater susceptibility to infection than burn alone. Alcohol-mediated immunomodulation contributes to tissue injury in target organs as described below.

    Gastrointestinal Tract

    A multitude of studies have demonstrated that the gut is a reservoir for pathogenic bacteria, which may contribute to increased susceptibility to infections following traumatic injury (Deitch 1990). The intestinal mucosal barrier serves a major role in the local defense against bacterial entry and the translocation of endotoxin to the systemic circulation (Xu et al. 1997). Increased permeability and immune dysfunction indicate the compromised state of the intestinal mucosal barrier to bacterial translocation following trauma (Deitch et al. 1990; Willoughby et al. 1996). Increased intestinal permeability enhances bacterial and endotoxin translocation from the intestinal tract to the systemic circulation, triggering a systemic inflammatory response (Xu et al. 1997). Activated macrophages and lymphocytes release pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6, thereby contributing to tissue injury (Fink 1991). Studies have determined that chronic alcohol consumption disrupts intestinal barrier function and induces gut leak (Li et al. 2008; Tang et al. 2009). In addition, reports have shown a loss of intestinal barrier function followed by an increase in endotoxin and bacterial translocation to the systemic circulation following burn injury alone (Carter et al. 1990; Deitch and Berg 1987; Horton 1994), alcohol intoxication alone (Keshavarzian et al. 1994; Tabata et al. 2002), and burn injury with alcohol intoxication (Choudhry et al. 2002; Kavanaugh et al. 2005; Napolitano et al. 1995). Acute alcohol intoxication at the time of burn injury enhances bacterial growth in the intestine and is reflected in a proportional increase in mesenteric lymph node bacterial count (Kavanaugh et al. 2005). Acute alcohol intoxication also modulates intestinal immune defense by suppressing T-cell proliferation and increasing bacterial accumulation in mesenteric lymph nodes, spleen, and blood, which suggests that T-cell suppression may play a role in bacterial translocation from the lumen of the gut (Choudhry et al. 2002). Moreover, studies have shown that following shock, trauma, or burn injury, the gut leaks bacteria and pro-inflammatory factors that are carried by the mesenteric lymphatic system, which contributes to acute lung injury (ALI) (Magnotti et al. 1999). The possibility that alcohol exacerbates toxin delivery to the systemic circulation through the lymphatics is supported by studies demonstrating that alcohol regulates the contractile cycle of mesenteric lymphatic vessels modulating the driving force of lymph flow (Keshavarzian et al. 1994; Souza-Smith et al. 2010). Thus, the contribution of gut–lymph to end-organ damage following burn injury and alcohol intoxication may be significant.

    Collectively, studies indicate that alcohol consumption preceding burn injury (1) increases gut permeability; (2) enhances intestinal bacterial growth, translocation, and systemic accumulation; and (3) suppresses T-cell proliferation. Further, research supports the concept that the intestine is not only a source of infection but also the site of the initial immune perturbation leading to the development of multiple organ dysfunction or organ failure.

    Cardiovascular System

    Immediately following a burn injury, the cardiovascular system responds with a decrease in cardiac output (Cuthbertson et al. 2001) as a result of low blood volume and reduced venous return (Kramer et al. 2007). This phase is associated with decreased cardiac contractility, mediated by the release of vasoactive and pro-inflammatory mediators (Williams et al. 2011). Subsequently, there is a surge in counterregulatory neuroendocrine mediators (catecholamines, glucagon, and cortisol) that contribute to the development of a hyperdynamic cardiovascular state—characterized by increased heart rate and cardiac output—and is associated with increased myocardial oxygen consumption and myocardial hypoxia (Williams et al. 2011). These pathophysiological processes enhance oxidative metabolism and increase the risk for free-radical generation, further exacerbating the pro-oxidative environment that has been proposed to contribute to impaired wound healing in burn patients (Herndon and Tompkins 2004). Chronic binge alcohol consumption also has been shown to promote a pro-oxidative and pro- inflammatory milieu (Rashbastep et al. 1993), and these factors may further impede wound healing in patients consuming alcohol prior to experiencing burn injury. Additional research is needed to better understand immunomodulation effects following the combined insults of alcohol and burn injury and the mechanisms underlying the more severe outcome of burn injury with alcohol abuse.

    Pulmonary System

    Adult respiratory distress syndrome (ARDS) is a frequent cause of death in burn patients. The lungs are one of the first organs to fail following traumatic injury (Turnage et al. 2002). Chronic and acute alcohol abuse impair pulmonary host defense to infection, thus increasing the risk of bacterial infection and acute lung injury (Boe et al. 2009; Happel and Nelson 2005). Lung injury as a result of the combination of alcohol intoxication and burn injury may be attributed to the delicate architecture of the lungs combined with other alcohol-related factors, such as bacterial and endotoxin leakage from the gut and a higher risk of contact with pathogens from the circulation and airways (Bird and Kovacs 2008; Li et al. 2007). Previous studies show that the combined insult of acute alcohol consumption and burn injury in mice leads to increased infiltration of the lungs by white blood cells, called neutrophils, and proinflammatory cytokine expression of IL-6 (Chen et al. 2013). Systemic and pulmonary IL-6 reflect the inflammatory state of the host and have been shown to be decreased in the absence of Toll-like receptor-4 (TLR-4) and intercellular adhesion molecule-1 (ICAM-1) (Bird et al. 2010). The role of IL-6 in lung injury has been demonstrated in studies in IL-6 knockout mice or following neutralization of IL-6, both of which result in significantly reduced lung inflammation (Chen et al. 2013). Studies also have shown that acute alcohol intoxication at the time of burn injury induces an upregulation of IL-18 production and neutrophil infiltration within the lung compartment, all leading to pulmonary edema (Li et al. 2007).

    Metabolism

    The post-burn period is characterized by a hypermetabolic state (Pereira and Herndon 2005) consisting of increased oxygen consumption; increased breakdown of glycogen, fats, and proteins; elevated resting energy expenditure and glucose synthesis; and reduced insulin-stimulated glucose uptake into skeletal muscle and adipose tissue (Gauglitz et al. 2009). Previous studies suggest that development of this hypermetabolic state during the post-burn period occurs as a consequence of (1) increased plasma catecholamine and corticosteroid concentrations (Jeschke et al. 2008; Williams et al. 2009; Wilmore and Aulick 1978), (2) increased systemic pro-inflammatory mediator expression, favoring processes that release energy (i.e., catabolic) over those that store energy (i.e., anabolic) (Jeschke et al. 2004), and (3) increased adipose tissue mRNA (Zhang et al. 2008) and protein (Yo et al. 2013) expression of uncoupling protein-1 (UCP-1), enhancing heat production and metabolism. Further, circulating levels of TNF-α, a known anti-insulin cytokine, are increased (Keogh et al. 1990), and the post-burn period can be described as a state of marked insulin resistance (IR) (Gauglitz et al. 2009). Insulin sensitivity has been reported to be decreased by more than 50 percent at 1-week post–burn injury in pediatric patients (Cree et al. 2007) as well as in rodent models of burn injury (Carter et al. 2004). The relevance of insulin levels to overall outcome from burn injury is supported by results from clinical studies showing that exogenous insulin therapy in pediatric burn patients decreased pro-inflammatory cytokines, increased anti-inflammatory cytokines, and increased serum concentrations of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3). Together, these changes could help to preserve organ function and better promote anabolic processes during the post-burn hypermetabolic state (Jeschke et al. 2004). Chronic alcohol consumption decreases insulin responsiveness and can alter insulin signaling through various mechanisms, including increased hepatic protein expression of the gene phosphatase and tensin homologue (PTEN), which directly inhibits insulin signaling through the phosphatidylinositol-5,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway (de la Monte et al. 2012). In addition to the negative regulation of the pathway by PTEN proteins, the enzyme protein tyrosine phosphatase dephosphorylates and decreases activity of important molecules involved in the insulin signaling cascade, potentially contributing to impaired insulin action (Gao et al. 2010; Koren and Fantus 2007). In addition, Lang and colleagues (2014) demonstrated that chronic alcohol consumption reduces Akt and AS160 phosphorylation, reduces membrane localization of glucose transporter type 4 (GLUT-4) protein, and increases serine phosphorylation at serine-307 of insulin receptor substrate-1 (IRS-1), all of which will attenuate insulin-stimulated skeletal muscle glucose uptake and other insulin-mediated anabolic effects (Lang et al. 2014). These negative effects on insulin signaling occurred in conjunction with sustained increases in pro inflammatory cytokines TNF-α and IL-6 following chronic alcohol exposure (Lang et al. 2014). Thus, both burn injury and chronic alcohol exposure alter metabolic pathways—favoring catabolic and opposing anabolic pathways—possibly resulting in long-lasting alterations in metabolic processes. The metabolic dysregulation following burn injury is likely to produce more severe consequences in chronic alcohol burn victims. Previous studies assessing nutritional status of alcoholic patients have been discordant, with some studies suggesting that increased alcohol consumption increases the prevalence of malnutrition in alcoholic patients (Hillers and Massey 1985), whereas other studies do not show a role for excessive, or chronic, alcohol consumption in malnutrition (Nicolas et al. 1993; Urbano-Marquez et al. 1989). A study assessing the influences of aging and chronic alcohol feeding in mice on protein synthesis demonstrated that chronic alcohol feeding decreases gastrocnemius muscle protein synthesis, which provides a mechanism for loss of lean body mass (Korzick et al. 2013; Lang et al. 2014). Decreased anabolism during the post-burn period, which itself is a state of heightened catabolic processes, could significantly impair recovery for these alcoholic patients experiencing burn injury. Further, the hypermetabolic state of the post-burn period is thought to contribute to delayed or impaired wound healing, increased susceptibility to infections, and erosion of lean body mass (Pereira and Herndon 2005). Moreover, both binge alcohol consumption (Pravdova and Fickova 2006; You and Rogers 2009) and burn injury (Venkatesh et al. 2009; Wade et al. 2013) can contribute to dysregulation of cytokines secreted by adipose tissue (i.e., adipokines). Recent studies show that mice exposed to a single alcohol binge prior to burn injury have a dramatic increase in pro-inflammatory response and a decrease in anti-inflammatory response in adipose tissue (Qin et al. 2014). The heightened pro-inflammatory response during the post-burn period would be predicted to modulate leptin levels. Thus, recovery from burn injury is likely to be severely impaired in alcoholic individuals as a result of a greater disruption in metabolic processes as well as impairment of host defense mechanisms, leading to greater morbidity and health care costs associated with the management of these patients. Therefore, further investigation is warranted to understand the modulation of the immune system by the combined effect of alcohol and burn that might result in dysregulation of adipose tissue and altered metabolism.

    Alcohol and Hemorrhagic Shock

    Studies from several investigators have provided evidence that traumatic injury and hemorrhagic shock produce an immediate upregulation of pro-inflammatory cytokine gene product expression (Ayala et al. 1991; Hierholzer et al. 1998). The early pro-inflammatory response is later followed by suppression of stimulated pro-inflammatory cytokine release (Angele et al. 1999; Xu et al. 1998) and alterations of both cellular and humoral immunity (Napolitano et al. 1995; Wichmann et al. 1998), leading to generalized immunosuppression, which ultimately results in an increased susceptibility to infection (Abraham 1993; Ertel et al. 1993). Along with marked alterations in hemodynamic homeostasis and neuroendocrine regulation, immunological derangements and subsequent infections are also a major cause of increased morbidity and mortality following hemorrhagic shock (Livingston and Malangoni 1988; Phelan et al. 2002).

    Studies focused on the immune modulatory effects of alcohol exposure following hemorrhagic shock have demonstrated that even 24 hours after the post-hemorrhagic shock, alcohol-intoxicated animals had a marked suppression in cytokine release to an inflammatory challenge (Greiffenstein et al. 2007), affecting the ability to fight secondary infectious challenges. Conversely, findings observed at the tissue level determined that alcohol intoxication enhanced the pro-inflammatory milieu following hemorrhagic shock, priming tissues for injury. The burden of alcohol and hemorrhagic shock on specific target organ systems is discussed below and summarized in figure 2.

     

    Image
    Salient gastrointestinal, pulmonary, and neuroendocrine pathophysiological consequences of alcohol abuse prior to, or at the time of, hemorrhagic shock.
    Figure 2 Salient gastrointestinal, pulmonary, and neuroendocrine pathophysiological consequences of alcohol abuse prior to, or at the time of, hemorrhagic shock. The decreased hemodynamic counterregulatory response leads to decreased tissue perfusion, accentuated oxidative stress, and enhanced tissue injury. In addition, the alcohol/hemorrhaged host shows greater susceptibility to secondary infections leading to increased morbidity and mortality during the post-injury period.

    Gastrointestinal Tract

    Hemorrhagic shock produces similar alterations in gut barrier function to those resulting from burn injury. Alcohol intoxication at the time of hemorrhagic shock further exacerbates hemorrhagic injury-induced gut permeability and leakage (Sulzer et al. 2013). Chronic alcohol consumption has been shown to disrupt intestinal barrier function and induce gut leak (Li et al. 2008; Tang et al. 2009). The combination of greater hypotension and inadequate tissue blood flow (i.e., hypoperfusion) observed in alcohol-intoxicated animals and the increased gut leak observed in alcohol-intoxicated hemorrhaged animals are speculated to contribute to increased host susceptibility to infection and tissue injury during recovery (Molina et al. 2013). Alcohol-intoxicated, hemorrhaged animals have been shown to have greater reduction in hepatic, renal, and intestinal blood flow than that observed in nonintoxicated animals (Sulzer et al. 2013). This reduction in critical organ blood flow was associated with enhanced tissue damage. An additional mechanism that could contribute to tissue injury in the alcohol-intoxicated, hemorrhaged host is the disruption of gut-associated lymphoid tissue function, which has been shown to play a role in other disease states.

    Cardiovascular System

    Studies using a rodent model of binge-like alcohol consumption prior to hemorrhagic shock have shown that acute alcohol intoxication decreases basal mean arterial blood pressure (MABP), exacerbates hypotension, and attenuates blood pressure recovery during fluid resuscitation (Mathis et al. 2006; Phelan et al. 2002). Following fixed-volume hemorrhage, alcohol-intoxicated animals were significantly more hypotensive throughout the hemorrhage and resuscitation periods (Mathis et al. 2006). In response to a fixed-pressure (40 mmHg) hemorrhage, a significantly lesser amount of blood was removed from the alcohol-intoxicated animals than controls (Phelan et al. 2002). Similarly, McDonough and colleagues, using a guinea pig model of ethanol exposure prior to hemorrhagic shock (loss of 60% blood volume) and resuscitation, demonstrated that a low dose of ethanol (1 g/kg) decreases MABP and heart rate and exacerbates the metabolic effects of hemorrhagic shock, as shown by increased glucose and lactate concentrations (McDonough et al. 2002). Despite the plethora of previous studies that have examined functional cardiovascular consequence of hemorrhagic shock and hemorrhage with alcohol intoxication, few studies have examined the combined effects of alcohol, hemorrhagic shock, and immune dysfunction on the cardiovascular system. However, exacerbation of pre-existing cardiovascular disease and prolonged recovery are anticipated outcomes of the combined effects of alcohol and hemorrhagic shock, all leading to an impaired immune response.

    Pulmonary System

    As mentioned previously, alcohol intoxication produces significant dysregulation of the host defense mechanism during the post-injury period. Lung IL-6 and TNF-α are suppressed, while granulocyte-colony stimulating factor (GCSF) mRNA is increased in alcohol-intoxicated, hemorrhaged animals (Mathis et al. 2006; Ono et al. 2004). Moreover, isolated pleural cells and peripheral blood mononuclear cells (PBMCs) from alcohol-intoxicated, hemorrhaged animals display suppressed TNF-α, IL-1β, and IL-6 release following lipopolysaccharide stimulation (Greiffenstein et al. 2007), suggesting greater impairment of humoral immune response than that resulting from hemorrhagic shock alone. The importance of these alterations in host defense mechanisms was demonstrated in animals inoculated with Klebsiella pneumonia following hemorrhagic shock. These studies showed suppressed neutrophil response, decreased phagocytic activity, and increased neutrophil apoptosis in hemorrhaged animals that were alcohol intoxicated at the time of injury (Zambell et al. 2004). This was associated with greater lung bacterial counts and prolonged elevation in TNF-α and IL-6 levels (18 h) post-infection. Furthermore, only 30 percent of alcohol-intoxicated, hemorrhaged animals survived compared with 70 percent survival of dextrose/hemorrhage animals (Zambell et al. 2004). In addition to cytokine dysregulation, alcohol impairs innate barrier functions of the lung by increasing epithelial cell permeability and altering the function of the ciliated epithelium (Elliott et al. 2007; Molina et al. 2010).

    Neuroendocrine System

    The pathophysiology of traumatic-hemorrhagic injury involves decreased blood volume (i.e., hypovolemia) and hypoperfusion, which results in signaling to central cardiovascular centers aimed at restoring hemodynamic stability through activation of descending autonomic neuroendocrine pathways (Molina 2005). Several mechanisms have been proposed to account for the increased hypotension and impaired hemodynamic stability observed with alcohol intoxication, with one proposed mechanism being blunted neuroendocrine activation. Studies demonstrated that acute alcohol intoxication at the time of injury results in significant attenuated release of counterregulatory hormones and potent vasoconstrictors such as arginine vasopressin (AVP), epinephrine, and norepinephrine in response to fixed-pressure hemorrhage (Phelan et al. 2002). A disruption in the neuroendocrine response with alcohol intoxication at the time of injury is associated with enhanced expression of lung and spleen TNF-α as well as suppression of circulating neutrophil function, which would be expected to enhance the risk for tissue injury (Whitaker et al. 2010). Conversely, Sato and colleagues (2013) demonstrated that alcohol aggravates hemorrhagic shock in a dose-dependent manner not by triggering an immune response but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic auto-regulation and shortening the survival interval. Thus, both alcohol and hemorrhagic shock have detrimental effects on neuroendocrine responses that are likely to modulate the host immune system in addition to impacting on hemodynamic stability and recovery and accentuating tissue hypoperfusion and end-organ injury.

    Alcohol and Traumatic Brain Injury

    Traumatic brain injury (TBI) accounts for approximately 50 percent of all trauma-related mortality (Centers for Disease Control and Prevention 2012b). TBI affects multiple sectors of the population, and young males have the highest rates of hospital visits and death (Faul et al. 2010). Falls are the first leading cause of TBI, followed by motor vehicle accidents and unintentional trauma sustained during sports activities such as football or boxing. TBI can be categorized as mild, moderate, or severe, and the majority of TBIs sustained in the United States are in the mild category (Centers for Disease Control and Prevention 2012b). In addition to the physical dysfunction caused by injury, TBI patients frequently experience lingering psychological symptoms, such as heightened anxiety, depression, sleep disturbances, and pain hypersensitivity (Whyte et al. 1996). These symptoms have been implicated in increased alcohol intake following TBI in humans (Adams et al. 2012). Furthermore, it is well accepted that alcohol consumption increases the risks of sustaining a TBI (Corrigan 1995; Hurst et al. 1994). Nevertheless, a comprehensive understanding of the influences of alcohol on TBI-induced inflammation, recovery from injury, and long-term damage currently is limited and is summarized in the following section (see figure 3).

     

    Image
    Salient cardiovascular, pulmonary, and central nervous system pathophysiological consequences of alcohol abuse prior to, or at the time of, traumatic brain injury (TBI).
    Figure 3 Salient cardiovascular, pulmonary, and central nervous system pathophysiological consequences of alcohol abuse prior to, or at the time of, traumatic brain injury (TBI). The disruption in hemodynamic homeostasis resulting from TBI contributes to decreased cerebral perfusion pressure. The lung is affected through neurogenic mechanisms leading to neuropulmonary edema (NPE) and associated risk for acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). In the brain (CNS), alcohol accentuates neuroinflammation, which is associated with neurobehavioral dysfunction that can potentially promote alcohol drinking. Together, these pathophysiological consequences increase morbidity and mortality from TBI.

    Neuroinflammation

    The pathophysiology of TBI involves a primary mechanical injury followed by a secondary tissue injury resulting from neuroinflammation (Werner and Engelhard 2007). A large percentage of TBI victims show signs of further deterioration following the event (Sauaia et al. 1995). This suggests the induction of a secondary brain injury and immune activation as the key cascades contributing to the pathophysiological processes of the secondary damage (Cederberg and Siesjo 2010). After TBI, a series of events occurs, including the activation of resident immune cells such as astrocytes and microglia, release of pro-inflammatory cytokines and chemokines, upregulation of endothelial adhesion molecules, and recruitment and activation of blood-derived leukocytes across the disrupted blood brain barrier (Feuerstein et al. 1998; Morganti-Kossmann et al. 2001; Ransohoff 2002). An increase in the levels of TNF-α in the serum or cerebrospinal fluid in victims of TBI also has been detected in rodents following closed head injury (Goodman et al. 1990; Ross et al. 1994; Shohami et al. 1994). IL-1β is released after TBI (Fan et al. 1995) and induces nuclear factor-kappa B (NF-κB), a key transcription factor that regulates the expression of genes encoding cytokines, as well as inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) (Blanco and Guerri 2007; Woodroofe et al. 1991; Ziebell and Morganti-Kossmann 2010). Following the rise of early cytokines, the release of IL-6 is associated with increased acute-phase proteins, as well as blood–brain barrier disruption (Kossmann et al. 1995; Shohami et al. 1994; Woodcock and Morganti-Kossmann 2013) and sustained elevation of chemokines such as chemokine (C-C motif) ligand-2 (CCL-2) in the cerebrospinal fluid for as long as 10 days post-injury (Semple et al. 2010). Although early cytokine release is essential in mediating the reparative processes after injury (Ziebell and Morganti-Kossmann 2010), sustained elevation of pro-inflammatory mediators has been increasingly recognized to play a role in neuropathological changes associated with long-term degenerative diseases (Fan et al. 1995; Lyman et al. 2014). Accordingly, the additional risks of alcohol as a factor contributing to the alterations of TBI-induced neuroinflammatory processes may affect the overall recovery.

    Alcohol exerts a profound impact on neuroinflammation. Although there are some conflicting reports in the literature about the role of alcohol on recovery, the major findings are summarized here. Some animal studies suggest that acute alcohol administration prior to TBI leads to an early reduction in the levels of pro-inflammatory cytokines and chemokines in the injured cortex, hippocampus, and hypothalamus, as well as in the serum shortly after TBI (Goodman et al. 2013; Gottesfeld et al. 2002). Recent studies also have confirmed that acute alcohol intoxication at the time of TBI does not exacerbate the expression of pro-inflammatory cytokines and chemokines at 6 hours post-injury. However, results obtained at a later time point (24 hours) show a sustained mRNA expression of IL-1β, TNF-α, IL-6, and CCL-2 following a lateral fluid percussion injury in rodents that were alcohol-intoxicated at the time of TBI (Teng and Molina 2014). Overall, some preclinical studies suggest that acute alcohol treatment prior to TBI may lead to a suppressed release of pro-inflammatory mediators during the early phase post-injury. Thus, the temporal pattern of neuroinflammatory responses and the impact of alcohol intoxication on neuroinflammatory responses are factors to consider when drawing conclusions on the role of alcohol in modulating the outcome from TBIs.

    Because the literature surrounding the relationship between acute alcohol intoxication and response to trauma is conflicting, it is important to consider the pattern of alcohol abuse and the model used in different studies. In general, reports in the literature indicate that chronic alcohol exposure produces immune activation in the brain, inducing an enhanced pro-inflammatory state, as evidenced by the presence of CCL-2 and microglial activation in postmortem brains of human alcoholics (He and Crews 2008). Animal studies show that chronic, intermittent binge alcohol administration to rodents results in increased microglial activation and inflammatory cytokine expression in the cortex and hippocampus (Zhao et al. 2013). In addition, Crews and colleagues (2004) have found that chronic alcohol treatment induces expression of inflammatory cytokines such as TNF-α, which further activates resident glial cells to secrete additional pro-inflammatory cytokines and chemokines, resulting in an increased immune activation in the brain. The overall pro-inflammatory effects of alcohol also have been shown by Guerri and colleagues (2007) who reported alcohol-mediated stimulation of TLR-4 and IL-1 receptor signaling pathways, including extracellular regulated-kinase 1/2 (ERK1/2), stress-activated protein kinase/c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinase (MAPK), as well as the expression of NF-kB, activator protein-1 (AP-1), iNOS, and COX-2 in cultured glial cells (Alfonso-Loeches et al. 2010; Fernandez-Lizarbe et al. 2009). The role of TLR4 has been identified in studies where 5 months of chronic alcohol administration increased glial activation and levels of caspase-3, iNOS, COX-2, and cytokines (IL-1β, TNF-α, and IL-6) in the cerebral cortex of wild-type mice but not in the TLR-4–deficient mice (Alfonso-Loeches et al. 2010). Another mediator of alcohol-mediated neuroinflammation is high-mobility group protein B1 (HMGB1), which has been reported to be increased along with TLR-2, TLR-3, and TLR-4 in postmortem brains of human alcoholics (Alfonso-Loeches et al. 2010). Despite a substantial amount of evidence showing increased neuroinflammatory responses to chronic alcohol exposure, there have not been sufficient preclinical studies performed to determine the combined effect of chronic alcohol consumption and TBI on neuroimmune activation. Because both TBI and alcohol can induce inflammation in the brain, we speculate that the combination of the two events would further accentuate neuroinflammation.

    Retrospective studies have revealed that outside of the central nervous system, peripheral organ damage can contribute to the increased mortality rate among TBI patients as a result of cardiovascular, pulmonary, and endocrine dysfunction (Gennarelli et al. 1989; Shavelle et al. 2001). More specifically, TBI patients have an increased incidence of ALI, pulmonary infection, neuroendocrine alterations, and cardiovascular dysfunction during the post-injury period (Vermeij et al. 2013). Although the combined effects of alcohol and TBI and the role of local or systemic immune responses in peripheral organs are understudied, the current knowledge is summarized below (figure 3).

    Pulmonary System

    ALI, one of the most common nonneurologic complications following TBI, results from acute pulmonary edema and inflammation and can lead to ARDS (Holland et al. 2003; Johnson and Matthay 2010). ALI is characterized by hypoxemia, loss of lung compliance, and bilateral chest infiltrates (Dushianthan et al. 2011). Development of ALI post-TBI has been associated with increased inpatient mortality following injury and worse long-term neurologic outcome in survivors of TBI (Bratton and Davis 1997; Holland et al. 2003). Post-TBI medical interventions including induced systemic hypertension and mechanical ventilation can result in nonneurogenic ALI (Contant et al. 2001; Lou et al. 2013). Development of neurogenic pulmonary edema (NPE) occurs minutes to hours following TBI and typically resolves within days (Bratton and Davis 1997). The possible underlying factors in NPE are the severity of injury leading to increased intracranial pressure and the subsequent increased circulating catecholamines (Demling and Riessen 1990). TBI also is associated with greater incidence of pulmonary infections than that seen following major surgeries, burn injury, and polytrauma (Dziedzic et al. 2004). Clinical reports indicate that over 40 percent of TBI patients with artificial ventilation develop pneumonia and are four times more likely to die from pneumonia (Harrison-Felix et al. 2006). The increased risk of developing pneumonia post-TBI is potentially attributed in part to a systemic immune response syndrome (SIRS) characterized by increased circulating pro-inflammatory cytokines (TNF-α and IL-6) (Keel and Trentz 2005; Kossmann et al. 1995).

    The combined impact of alcohol and TBI on pulmonary infections has been minimally investigated. Although, epidemiological studies have shown that in trauma patients, chronic alcohol abuse can independently increase the risk of ALI and ARDS two- to fourfold (Guidot and Hart 2005). In a prospective study of traumatic injury patients with evidence of acute alcohol intoxication or chronic alcohol abuse, chronic alcohol was associated with increased incidence of pneumonia or respiratory failure as a result of its immunosuppressive effects. However, no significant increase in incidence of pneumonia or respiratory failure and mortality was observed in patients with acute alcohol intoxication with BAC above 100mg/dL (De Guise et al. 2009; Jurkovich et al. 1993). The importance of length and amount of pre-existing alcohol intake and TBI severity may be the key factors in determining a patient’s risk for pneumonia. Taken together, the potential effects of chronic alcohol abuse and TBI could potentiate and further increase immunosuppression or immune dysfunction, thus leading to greater susceptibility for pneumonia, ARDS, and ultimately death.

    Neuroendocrine System

    TBI can lead to a variety of neuroendocrine abnormalities, such as gonadotropin deficiency, growth hormone deficiency, corticotrophin deficiency, and vasopressin alterations (Behan and Agha 2007; Powner and Boccalandro 2008). As a result of the mechanical compression to the pituitary gland or disruption of the pituitary stalk, hypopituitarism can occur and corticotrophin insufficiency is commonly observed after TBI (Agha et al. 2004; Cohan et al. 2005). Excessive alcohol use also has been reported to be associated with neuroendocrine dysfunction, notably in the form of altered regulation of hypothalamic–pituitary–adrenal axis (HPA), resulting in a decreased corticotrophin release (Behan and Agha 2007; Helms et al. 2014). Therefore, it is possible that the combination of alcohol and TBI-induced HPA dysfunction can lead to a dampened cortisol release, which may have an impact on the immune system. Interestingly, a hyperadrenergic state marked by elevated levels of catecholamines can occur after TBI, and alcohol intoxication at the time of TBI has been shown to blunt the sympatho-adrenal activation in a dose-dependent manner (Woolf et al. 1990). Vasopressin has been suggested to play a role in blood brain barrier disruption, edema formation, and the production of pro-inflammatory mediators after TBI (Szmydynger- Chodobska et al. 2010). Vasopressin abnormalities leading to diabetes insipidus or the syndrome of inappropriate anti-diuretic hormone (SIADH) frequently are observed after TBI (Behan and Agha 2007), and acute alcohol intoxication is known to alter AVP release (Taivainen et al. 1995). Whether alcohol intoxication at the time of TBI or during the recovery period from TBI further dysregulates these neuroendocrine mechanisms remains to be examined.

    Cardiovascular System

    Cardiovascular complications including slow heart rate (i.e., bradycardia), hypotension, electrocardiographic changes, arrhythmias, and increased circulating cardiac enzymes have been reported following TBI (Bourdages et al. 2010; Wittebole et al. 2005). Chronic alcohol abuse alone can lead to alcoholic cardiomyopathy and potentially heart failure (Skotzko et al. 2009), and the underlying etiology has been reviewed (Lang et al. 2005). Several studies by Zink and colleagues (1998a,b, 2006) focused on the combined effects of acute alcohol intoxication on hemorrhagic shock and TBI in swine, showing decreased survival time, lowered MABP, and reduced cerebral perfusion pressure, which may worsen secondary brain injury. These studies did not investigate alterations in immune function or expression and levels of immune modulators or their actions on cardiovascular function. Overall, the post-TBI cardiovascular complications, including vascular function, have been understudied in both clinical and experimental models of TBI. More specifically, the combined impact of alcohol, TBI, and immune alterations on cardiovascular dysfunction and disease progression has not been examined. A possible prediction is that chronic alcohol-induced immunosuppression would worsen post-TBI cardiovascular complications; and in chronic alcoholics, dilated cardiomyopathy may compound TBI-related cardiovascular complications increasing morbidity and mortality.

    Summary

    The deleterious effects of alcohol on the immune system in three traumatic injuries are discussed in this review and are summarized in figures 1, 2, and 3. It is evident that, independently, acute or chronic alcohol consumption and traumatic injury negatively modulate the immune system, and the end result is an uncontrolled release of inflammatory mediators. The most important message of this review is the accumulation of evidence that alcohol combined with traumatic injury can significantly affect morbidity and mortality through disruption in host immune responses. Following burn injury, for instance, the risk for infection is greatly increased because of increased gut permeability and increased pro-inflammatory cytokine expression in the lungs (figure 1). Alcohol use following hemorrhage can increase inflammation and oxidative stress in the gut while decreasing lung barrier function and subsequently increasing susceptibility to infection (figure 2). In the central nervous system, alcohol use following TBI can increase neuroinflammation and prolong the recovery period (figure 3). Overall this information is important, because it provides a wealth of evidence that alcohol combined with trauma is a dramatic and preventable cause of increased morbidity and mortality following injury. Mechanistically, two common pro-inflammatory cytokines that are consistently upregulated in all burn injury, hemorrhagic shock, and TBI are TNF-α and IL-6. A fuller understanding of their temporal pattern of expression and downstream effects requires further investigation. Although the studies described in this review have generated important information on the impact of alcohol combined with different types of traumatic injury, and the resultant adverse effects on the immune system, further preclinical and clinical studies to dissect the complex cascade of immunomodulation following injury are necessary. Specifically, further investigation is warranted to determine the underlying mechanisms involved in immune modulation by acute or chronic alcohol intake and the effects on (1) metabolism and the cardiovascular system following burn, (2) the neuroendocrine system following hemorrhagic shock, and (3) neuroinflammation and the neuroendocrine system following traumatic injury. The responses of the immune system to these inflammatory stimuli are variable and appear to be dependent on the severity of the injury, comorbidities, and the level of alcohol intoxication. Thus, it is necessary to systemically address these variables for translational research to identify potential therapeutic strategies. Furthermore, therapeutic targets for immunomodulation and attenuation of tissue injury in intoxicated and injured patients are likely to reduce morbidity and mortality and improve post-injury quality of life among these patients.

     

     

    Acknowledgments

    We thank Dr. Liz Simon for her intellectual contribution to this review and Rebecca Gonzales for her editorial support.

    Disclosures

    The authors declare that they have no competing financial interests.

    References

    Abraham, E. T- and B-cell function and their roles in resistance to infection. New Horizons 1(1):28–36, 1993. PMID: 7922390

    Adams, Z.W.; Kaiser, A.J.; Lynam, D.R.; et al. Drinking motives as mediators of the impulsivity-substance use relation: Pathways for negative urgency, lack of premeditation, and sensation seeking. Addictive Behaviors 37(7):848–855, 2012. PMID: 22472524

    Agha, A.; Rogers, B.; Mylotte, D.; et al. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clinical Endocrinology 60(5):584–591, 2004. PMID: 15104561

    Alfonso-Loeches, S.; Pascual-Lucas, M.; Blanco, A.M.; et al. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. Journal of Neuroscience 30(24):8285–8295, 2010. PMID: 20554880

    Angele, M.K.; Knoferl, M.W.; Schwacha, M.G.; et al. Hemorrhage decreases macrophage inflammatory protein 2 and interleukin-6 release: A possible mechanism for increased wound infection. Annals of Surgery 229(5):651–660; discussion 660–661, 1999. PMID: 10235523

    Arbabi, S.; Garcia, I.; Bauer, G.J.; and Maier, R.V. Alcohol (ethanol) inhibits IL-8 and TNF: Role of the p38 pathway. Journal of Immunology 162(12):7441–7445, 1999. PMID: 10358198

    Ayala, A.; Wang, P.; Ba, Z.F.; et al. Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. American Journal of Physiology 260(1 Pt. 2):R167–R171, 1991. PMID: 1992817

    Baker, C.C.; Oppenheimer, L.; Stephens, B.; et al. Epidemiology of trauma deaths. American Journal of Surgery 140(1):144–150, 1980. PMID: 7396078

    Baker, R.C., and Jerrells, T.R. Recent developments in alcoholism: Immunological aspects. Recent Developments in Alcoholism 11:249–271, 1993. PMID: 8234926

    Beech, D.J., and Mercadel, R. Correlation of alcohol intoxication with life-threatening assaults. Journal of the National Medical Association 90(12):761–764, 1998. PMID: 9884496

    Behan, L.A., and Agha, A. Endocrine consequences of adult traumatic brain injury. Hormone Research 68(Suppl. 5):18–21, 2007. PMID: 18174698

    Bessey, P.Q.; Phillips, B.D.; Lentz, C.W.; et al. Synopsis of the 2013 annual report of the National Burn Repository. Journal of Burn Care & Research 35(Suppl. 2):S218–S234, 2014. PMID: 24642761

    Bird, M.D., and Kovacs, E.J. Organ-specific inflammation following acute ethanol and burn injury. Journal of Leukocyte Biology 84(3):607–613, 2008. PMID: 18362209

    Bird, M.D.; Morgan, M.O.; Ramirez, L.; et al. Decreased pulmonary inflammation after ethanol exposure and burn injury in intercellular adhesion molecule-1 knockout mice. Journal of Burn Care & Research 31(4):652–660, 2010. PMID: 20616655

    Blanco, A.M., and Guerri, C. Ethanol intake enhances inflammatory mediators in brain: Role of glial cells and TLR4/IL-1RI receptors. Frontiers in Bioscience 12:2616–2630, 2007. PMID: 17127267

    Boe, D.M.; Vandivier, R.W.; Burnham, E.L.; and Moss, M. Alcohol abuse and pulmonary disease. Journal of Leukocyte Biology 86(5):1097–1104, 2009. PMID: 19602670

    Bourdages, M.; Bigras, J.L.; Farrell, C.A.; et al. Cardiac arrhythmias associated with severe traumatic brain injury and hypothermia therapy. Pediatric Critical Care Medicine 11(3):408–414, 2010. PMID: 20464781

    Bratton, S.L., and Davis, R.L. Acute lung injury in isolated traumatic brain injury. Neurosurgery 40(4):707–712; discussion 712, 1997. PMID: 9092843

    Brown, L.A.; Cook, R.T.; Jerrells, T.R.; et al. Acute and chronic alcohol abuse modulate immunity. Alcoholism: Clinical and Experimental Research 30(9):1624–1631, 2006. PMID: 16930226

    Brown, L.A.; Ping, X.D.; Harris, F.L.; and Gauthier, T.W. Glutathione availability modulates alveolar macrophage function in the chronic ethanol-fed rat. American Journal of Physiology. Lung Cellular and Molecular Physiology 292(4):L824–L832, 2007. PMID: 17122355

    Carter, E.A.; Burks, D.; Fischman, A.J.; et al. Insulin resistance in thermally-injured rats is associated with post-receptor alterations in skeletal muscle, liver and adipose tissue. International Journal of Molecular Medicine 14(4):653–658, 2004. PMID: 15375597

    Carter, E.A.; Tompkins, R.G.; Schiffrin, E.; and Burke, J.F. Cutaneous thermal injury alters macromolecular permeability of rat small intestine. Surgery 107(3):335–341, 1990. PMID: 2309150

    Cederberg, D., and Siesjo, P. What has inflammation to do with traumatic brain injury? Child’s Nervous System 26:221–226, 2010. PMID: 19940996

    Centers for Disease Control and Prevention (CDC). Web-based Injury Statistics Query and Reporting System 2009. Atlanta: CDC, 2009. Available at: http://www.cdc.gov/injury/wisqars/pdf/leading_causes_of_death_by_age_group_2012-a.pdf. Accessed March 3, 2015.

    Centers for Disease Control and Prevention. CDCChronic DiseaseExcessive Alcohol UseAt a Glance. Atlanta: CDC, 2012a. Available at: http://www.cdc.gov/alcohol. Accessed March 3, 2015.

    Centers for Disease Control and Prevention. CDCStatisticsInjury Prevention & Control: Traumatic Brain Injury. Atlanta: CDC, 2012b. Available at: http://www.cdc.gov/traumaticbraininjury/. Accessed March 3, 2015.

    Chen, M.M.; Bird, M.D.; Zahs, A.; et al. Pulmonary inflammation after ethanol exposure and burn injury is attenuated in the absence of IL-6. Alcohol 47(3):223–229, 2013. PMID: 23462222

    Choudhry, M.A.; Fazal, N.; Goto, M.; et al. Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury. American Journal of Physiology. Gastrointestinal and Liver Physiology 282(6):G937–G947, 2002. PMID: 12016118

    Choudhry, M.A.; Messingham, K.A.; Namak, S.; et al. Ethanol exacerbates T cell dysfunction after thermal injury. Alcohol 21(3):239–243, 2000. PMID: 11091027

    Cohan, P.; Wang, C.; McArthur, D.L.; et al. Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study. Critical Care Medicine 33(10):2358–2366, 2005. PMID: 16215393

    Contant, C.F.; Valadka, A.B.; Gopinath, S.P.; et al. Adult respiratory distress syndrome: A complication of induced hypertension after severe head injury. Journal of Neurosurgery 95(4):560–568, 2001. PMID: 11596949

    Corrigan, J.D. Substance abuse as a mediating factor in outcome from traumatic brain injury. Archives of Physical Medicine and Rehabilitation 76(4):302–309, 1995. PMID: 7717829

    Cree, M.G.; Zwetsloot, J.J.; Herndon, D.N.; et al. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. Annals of Surgery 245(2):214–221, 2007. PMID: 17245174

    Crews, F.T.; Collins, M.A.; Dlugos, C.; et al. Alcohol-induced neurodegeneration: When, where and why? Alcoholism: Clinical and Experimental Research 28(2):350–364, 2004. PMID: 15112943

    Cuthbertson, D.P.; Angeles Valero Zanuy, M.A.; and León Sanz, M.L. Post-shock metabolic response, 1942. Nutrición Hospitalaria 16(5):176–182; discussion 175–176, 2001. PMID: 11708288

    De Guise, E.; Leblanc, J.; Dagher, J.; et al. Early outcome in patients with traumatic brain injury, pre-injury alcohol abuse and intoxication at time of injury. Brain Injury 23(11):853–865, 2009. PMID: 20100121

    de la Monte, S.; Derdak, Z.; and Wands, J.R. Alcohol, insulin resistance and the liver-brain axis. Journal of Gastroenterology and Hepatology 27(Suppl. 2):33–41, 2012. PMID: 22320914

    Deitch, E.A. The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Archives of Surgery 125(3):403–404, 1990. PMID: 2407230

    Deitch, E.A., and Berg, R. Bacterial translocation from the gut: A mechanism of infection. Journal of Burn Care & Rehabilitation 8(6):475–482, 1987. PMID: 3125184

    Deitch, E.A.; Morrison, J.; Berg, R.; and Specian, R.D. Effect of hemorrhagic shock on bacterial translocation, intestinal morphology, and intestinal permeability in conventional and antibiotic-decontaminated rats. Critical Care Medicine 18(5):529–536, 1990. PMID: 2328600

    Demling, R., and Riessen, R. Pulmonary dysfunction after cerebral injury. Critical Care Medicine 18(7):768–774, 1990. PMID: 2194747

    D’Souza, N.B.; Bagby, G.J.; Nelson, S.; et al. Acute alcohol infusion suppresses endotoxin-induced serum tumor necrosis factor. Alcoholism: Clinical and Experimental Research 13(2):295–298, 1989. PMID: 2658671

    Dushianthan, A.; Grocott, M.P.; Postle, A.D.; and Cusack, R. Acute respiratory distress syndrome and acute lung injury. Postgraduate Medicine Journal 87(1031):612–622, 2011. PMID: 21642654

    Dziedzic, T.; Slowik, A.; and Szczudlik, A. Nosocomial infections and immunity: Lesson from brain-injured patients. Critical Care 8:266–270, 2004. PMID: 15312209

    Elliott, M.K.; Sisson, J.H.; and Wyatt, T.A. Effects of cigarette smoke and alcohol on ciliated tracheal epithelium and inflammatory cell recruitment. American Journal of Respiratory Cell and Molecular Biology 36(4):452–459, 2007. PMID: 17079783

    Ertel, W.; Singh, G.; Morrison, M.H.; et al. Chemically induced hypotension increases PGE2 release and depresses macrophage antigen presentation. American Journal of Physiology 264(4 Pt. 2):R655–R660, 1993. PMID: 8476108

    Fan, L.; Young, P.R.; Barone, F.C.; et al. Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Brain Research. Molecular Brain Research 30(1):125–130, 1995. PMID: 7609633

    Faul, M.; Xu, L.; Wald, M.M.; et al. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. Atlanta, GA: U.S. Department of Health and Human Services, CDC, 2010. Available at: http://www.cdc.gov/traumaticbraininjury/pdf/blue_book.pdf. Accessed March 3, 2015.

    Faunce, D.E.; Garner, J.L.; Llanas, J.N.; et al. Effect of acute ethanol exposure on the dermal inflammatory response after burn injury. Alcoholism: Clinical and Experimental Research 27(7):1199–1206, 2003. PMID: 12878929

    Faunce, D.E.; Gregory, M.S.; and Kovacs, E.J. Acute ethanol exposure prior to thermal injury results in decreased T-cell responses mediated in part by increased production of IL-6. Shock 10(2):135–140, 1998. PMID: 9721981

    Faunce, D.E.; Gregory, M.S.; and Kovacs, E.J. Effects of acute ethanol exposure on cellular immune responses in a murine model of thermal injury. Journal of Leukocyte Biology 62(6):733–740, 1997. PMID: 9400814

    Fernandez-Lizarbe, S.; Pascual, M.; and Guerri, C. Critical role of TLR4 response in the activation of microglia induced by ethanol. Journal of Immunology 183(7):4733–4744, 2009. PMID: 19752239

    Feuerstein, G.Z.; Wang, X.; and Barone, F.C. The role of cytokines in the neuropathology of stroke and neurotrauma. Neuroimmunomodulation 5(3–4):143–159, 1998. PMID: 9730680

    Fink, M.P. Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis. Critical Care Medicine 19(5):627–641, 1991. PMID: 2026025

    Gao, L.; Zhang, X.; Wang, F.R.; et al. Chronic ethanol consumption up-regulates protein-tyrosine phosphatase-1B (PTP1B) expression in rat skeletal muscle. Acta Pharmacologica Sinica 31(12):1576–1582, 2010. PMID: 21102485

    Gauglitz, G.G.; Herndon, D.N.; Kulp, G.A.; et al. Abnormal insulin sensitivity persists up to three years in pediatric patients post-burn. Journal of Clinical Endocrinology and Metabolism 94(5):1656–1664, 2009. PMID: 19240154

    Gennarelli, T.A.; Champion, H.R.; Sacco, W.J.; et al. Mortality of patients with head injury and extracranial injury treated in trauma centers. Journal of Trauma 29(9):1193–1201; discussion 1201–1202, 1989. PMID: 2769804

    Goodman, J.C.; Robertson, C.S.; Grossman, R.G.; and Narayan, R.K. Elevation of tumor necrosis factor in head injury. Journal of Neuroimmunology 30(2):213–217, 1990. PMID: 2229409

    Goodman, M.D.; Makley, A.T.; Campion, E.M.; et al. Preinjury alcohol exposure attenuates the neuroinflammatory response to traumatic brain injury. Journal of Surgical Research 184(2):1053–1058, 2013. PMID: 23721933

    Gottesfeld, Z.; Moore, A.N.; and Dash, P.K. Acute ethanol intake attenuates inflammatory cytokines after brain injury in rats: A possible role for corticosterone. Journal of Neurotrauma 19(3):317–326, 2002. PMID: 11939499

    Greiffenstein, P.; Mathis, K.W.; Stouwe, C.V.; and Molina, P.E. Alcohol binge before trauma/hemorrhage impairs integrity of host defense mechanisms during recovery. Alcoholism: Clinical and Experimental Research 31(4):704–715, 2007. PMID: 17374050

    Guidot, D.M., and Hart, C.M. Alcohol abuse and acute lung injury: Epidemiology and pathophysiology of a recently recognized association. Journal of Investigative Medicine 53(5):235–245, 2005. PMID: 16042957

    Gurney, J.G.; Rivara, F.P.; Mueller, B.A.; et al. The effects of alcohol intoxication on the initial treatment and hospital course of patients with acute brain injury. Journal of Trauma 33(5):709–713, 1992. PMID: 1464920

    Happel, K.I., and Nelson, S. Alcohol, immunosuppression, and the lung. Proceedings of the American Thoracic Society 2(5):428–432, 2005. PMID: 16322595

    Harrison-Felix, C.; Whiteneck, G.; Devivo, M.J.; et al. Causes of death following 1 year postinjury among individuals with traumatic brain injury. Journal of Head Trauma Rehabilitation 21(1):22–33, 2006. PMID: 16456389

    Haum, A.; Perbix, W.; Hack, H.J.; et al. Alcohol and drug abuse in burn injuries. Burns 21(3):194–199, 1995. PMID: 7794500

    He, J., and Crews, F.T. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Experimental Neurology 210(2):349–358, 2008. PMID: 18190912

    Helms, C.M.; Park, B.; and Grant, K.A. Adrenal steroid hormones and ethanol self-administration in male rhesus macaques. Psychopharmacology (Berlin) 231(17):3425–3436, 2014. PMID: 24781519

    Herndon, D.N., and Tompkins, R.G. Support of the metabolic response to burn injury. Lancet 363(9424):1895–1902, 2004. PMID: 15183630

    Hierholzer, C.; Kalff, J.C.; Omert, L.; et al. Interleukin-6 production in hemorrhagic shock is accompanied by neutrophil recruitment and lung injury. American Journal of Physiology 275(3 Pt. 1):L611–L621, 1998. PMID: 9728057

    Hillers, V.N., and Massey, L.K. Interrelationships of moderate and high alcohol consumption with diet and health status. American Journal of Clinical Nutrition 41(2):356–362, 1985. PMID: 3969943

    Holland, M.C.; Mackersie, R.C.; Morabito, D.; et al. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. Journal of Trauma 55(1):106–111, 2003. PMID: 12855888

    Horton, J.W. Bacterial translocation after burn injury: The contribution of ischemia and permeability changes. Shock 1(4):286–290, 1994. PMID: 7735963

    Hurst, P.M.; Harte, D.; and Frith, W.J. The Grand Rapids dip revisited. Accident: Analysis and Prevention 26(5): 647–654, 1994. PMID: 7999209

    Jeschke, M.G.; Barrow, R.E.; and Herndon, D.N. Extended hypermetabolic response of the liver in severely burned pediatric patients. Archives of Surgery 139(6):641–647, 2004. PMID: 15197091

    Jeschke, M.G.; Chinkes, D.L.; Finnerty, C.C.; et al. Pathophysiologic response to severe burn injury. Annals of Surgery 248(3):387–401, 2008. PMID: 18791359

    Johnson, E.R., and Matthay, M.A. Acute lung injury: Epidemiology, pathogenesis, and treatment. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23(4): 243–252, 2010. PMID: 20073554

    Jurkovich, G.J.; Rivara, F.P.; Gurney, J.G.; et al. The effect of acute alcohol intoxication and chronic alcohol abuse on outcome from trauma. JAMA 270(1):51–56, 1993. PMID: 8510296

    Jurkovich, G.J.; Rivara, F.P.; Gurney, J.G.; et al. Effects of alcohol intoxication on the initial assessment of trauma patients. Annals of Emergency Medicine 21(6):704–708, 1992. PMID: 1590611

    Kavanaugh, M.J.; Clark, C.; Goto, M.; et al. Effect of acute alcohol ingestion prior to burn injury on intestinal bacterial growth and barrier function. Burns 31(3):290–296, 2005. PMID: 15774282

    Keel, M., and Trentz, O. Pathophysiology of polytrauma. Injury 36(6):691–709, 2005. PMID: 15910820

    Keogh, C.; Fong, Y.; Marano, M.A.; et al. Identification of a novel tumor necrosis factor alpha/cachectin from the livers of burned and infected rats. Archives of Surgery 125(1):79–84; discussion 85, 1990. PMID: 2104745

    Keshavarzian, A.; Fields, J.Z.; Vaeth, J.; and Holmes, E.W. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. American Journal of Gastroenterology 89(12):2205–2211, 1994. PMID: 7977243

    Koren, S., and Fantus, I.G. Inhibition of the protein tyrosine phosphatase PTP1B: Potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Practice & Research. Clinical Endocrinology & Metabolism 21(4):621–640, 2007. PMID: 18054739

    Korzick, D.H.; Sharda, D.R.; Pruznak, A.M.; and Lang, C.H. Aging accentuates alcohol-induced decrease in protein synthesis in gastrocnemius. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 304(10):R887–R898, 2013. PMID: 23535459

    Kossmann, T.; Hans, V.H.; Imhof, H.G.; et al. Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 4(5):311–317, 1995. PMID: 8595516

    Kramer, G.C.; Lund, T.; and Beckum, O. Pathophysiology of burn shock and burn edema. In: Herndon, D.N., Ed. Total Burn Care, 3rd ed. London: Saunders, 2007, pp. 93–106.

    Lang, C.H.; Derdak, Z.; and Wands, J.R. Strain-dependent differences for suppression of insulin-stimulated glucose uptake in skeletal and cardiac muscle by ethanol. Alcoholism: Clinical and Experimental Research 38(4): 897–910, 2014. PMID: 22460535

    Lang, C.H.; Frost, R.A.; Summer, A.D.; and Vary, T.C. Molecular mechanisms responsible for alcohol-induced myopathy in skeletal muscle and heart. International Journal of Biochemistry & Cell Biology 37(10):2180–2195, 2005. PMID: 15982919

    Li, X.; Kovacs, E.J.; Schwacha, M.G.; et al. Acute alcohol intoxication increases interleukin-18-mediated neutrophil infiltration and lung inflammation following burn injury in rats. American Journal of Physiology. Lung Cellular and Molecular Physiology 292(5):L1193–L1201, 2007. PMID: 17220368

    Li, X.; Schwacha, M.G.; Chaudry, I.H.; and Choudhry, M.A. Acute alcohol intoxication potentiates neutrophil-mediated intestinal tissue damage after burn injury. Shock 29(3):377–383, 2008. PMID: 18000475

    Livingston, D.H., and Malangoni, M.A. Interferon-gamma restores immune competence after hemorrhagic shock. Journal of Surgery Research 45(1):37–43, 1988. PMID: 3134579

    Lou, M.; Chen, X.; Wang, K.; et al. Increased intracranial pressure is associated with the development of acute lung injury following severe traumatic brain injury. Clinical Neurology and Neurosurgery 115(7):904–908, 2013. PMID: 23010612

    Lyman, M.; Lloyd, D.G.; Ji, X.; et al. Neuroinflammation: The role and consequences. Neuroscience Research 79:1–2, 2014. PMID: 24144733

    Madden, K.S.; Sanders, V.M.; and Felten, D.L. Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annual Review of Pharmacology and Toxicology 35:417–448, 1995. PMID: 7598501

    Magnotti, L.J.; Xu, D.Z.; Lu, Q.; and Deitch, E.A. Gut-derived mesenteric lymph: A link between burn and lung injury. Archives of Surgery 134(12):1333–1340; discussion 1340–1341, 1999. PMID: 10593331

    Mathis, K.W.; Zambell, K.; Olubadewo, J.O.; and Molina, P.E. Altered hemodynamic counter-regulation to hemorrhage by acute moderate alcohol intoxication. Shock 26(1):55–61, 2006. PMID: 16783199

    McDonough, K.H.; Giaimo, M.E.; Miller, H.I.; and Gentilello, L.M. Low-dose ethanol alters the cardiovascular, metabolic, and respiratory compensation for severe blood loss. Journal of Trauma 53(3):541–548; discussion 548, 2002. PMID: 12352494

    McGill, V.; Kowal-Vern, A.; Fisher, S.G.; et al. The impact of substance use on mortality and morbidity from thermal injury. Journal of Trauma 38(6):931–934, 1995. PMID: 7602638

    McGwin, G., Jr.; Chapman, V.; Rousculp, M.; et al. The epidemiology of fire-related deaths in Alabama, 1992–1997. Journal of Burn Care & Rehabilitation 21(1 Pt. 1):75–83, 2000. PMID: 10661543

    Mehta, A.J., and Guidot, D.M. Alcohol abuse, the alveolar macrophage and pneumonia. American Journal of the Medical Science 343(3):244–247, 2012. PMID: 22173040

    Messingham, K.A.; Faunce, D.E.; and Kovacs, E.J. Alcohol, injury, and cellular immunity. Alcohol 28(3): 137–149, 2002. PMID: 12551755

    Messingham, K.A.; Fontanilla, C.V.; Colantoni, A.; et al. Cellular immunity after ethanol exposure and burn injury: Dose and time dependence. Alcohol 22(1):35–44, 2000. PMID: 11109026

    Molina, P.E. Neurobiology of the stress response: Contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury. Shock 24(1):3–10, 2005. PMID: 15988314

    Molina, P.E.; Bagby, G.J.; and Stahls, P. Hemorrhage alters neuroendocrine, hemodynamic, and compartment-specific TNF responses to LPS. Shock 16(6):459–465, 2001. PMID: 11770045

    Molina, P.E.; Happel, K.I.; Zhang, P.; et al. Focus on: Alcohol and the immune system. Alcohol Research & Health 33(1):97–108, 2010. PMID: 23579940

    Molina, P.E.; Sulzer, J.K.; and Whitaker, A.M. Alcohol abuse and the injured host: Dysregulation of counterregulatory mechanisms review. Shock 39(3):240–249, 2013. PMID: 23416555

    Morganti-Kossmann, M.C.; Rancan, M.; Otto, V.I.; et al. Role of cerebral inflammation after traumatic brain injury: A revisited concept. Shock 16(3):165–177, 2001. PMID: 11531017

    Napolitano, L.M.; Koruda, M.J.; Zimmerman, K.; et al. Chronic ethanol intake and burn injury: Evidence for synergistic alteration in gut and immune integrity. Journal of Trauma 38(2):198–207, 1995. PMID: 7869435

    Nelson, S.; Bagby, G.; Andresen, J.; et al. The effects of ethanol, tumor necrosis factor, and granulocyte colony-stimulating factor on lung antibacterial defenses. Advances in Experimental Medicine and Biology 288:245–253, 1991. PMID: 1719751

    Nicolas, J.M.; Estruch, R.; Antunez, E.; et al. Nutritional status in chronically alcoholic men from the middle socioeconomic class and its relation to ethanol intake. Alcohol and Alcoholism 28(5):551–558, 1993. PMID: 8274179

    Nicolas, J.M.; Fernandez-Sola, J.; Fatjo, F.; et al. Increased circulating leptin levels in chronic alcoholism. Alcoholism: Clinical and Experimental Research 25(1):83–88, 2001. PMID: 11198718

    Nilsson, E., and Palmblad, J. Effects of ethanol on mechanisms for secretory and aggregatory responses of human granulocytes. Biochemical Pharmacology 37(17):3237–3243, 1988. PMID: 2840909

    Ono, M.; Yu, B.; Hardison, E.G.; et al. Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: Role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor. Shock 21(6):519–525, 2004. PMID: 15167680

    Patel, M.; Keshavarzian, A.; Kottapalli, V.; et al. Human neutrophil functions are inhibited in vitro by clinically relevant ethanol concentrations. Alcoholism: Clinical and Experimental Research 20(2):275–283, 1996. PMID: 8730218

    Peitzman, A.B.; Billiar, T.R.; Harbrecht, B.G.; et al. Hemorrhagic shock. Current Problems in Surgery 32(11):925–1002, 1995. PMID: 7587344

    Pereira, C.T., and Herndon, D.N. The pharmacologic modulation of the hypermetabolic response to burns. Advances in Surgery 39:245–261, 2005. PMID: 16250555

    Phelan, H.; Stahls, P.; Hunt, J.; et al. Impact of alcohol intoxication on hemodynamic, metabolic, and cytokine responses to hemorrhagic shock. Journal of Trauma 52(4):675–682, 2002. PMID: 11956381

    Pories, S.E.; Gamelli, R.L.; Vacek, P.; et al. Intoxication and injury. Journal of Trauma 32(1):60–64, 1992. PMID: 1732576

    Powner, D.J., and Boccalandro, C. Adrenal insufficiency following traumatic brain injury in adults. Current Opinion in Critical Care 14(2):163–166, 2008. PMID: 18388678

    Pravdova, E., and Fickova, M. Alcohol intake modulates hormonal activity of adipose tissue. Endocrine Regulations 40(3):91–104, 2006. PMID: 17100551

    Qin, Y.; Hamilton, J.L.; Bird, M.D.; et al. Adipose inflammation and macrophage infiltration after binge ethanol and burn injury. Alcoholism: Clinical and Experimental Research 38(1):204–213, 2014. PMID: 23909743

    Ransohoff, R.M. The chemokine system in neuroinflammation: An update. Journal of Infectious Diseases 186(Suppl. 2):S152–S156, 2002. PMID: 12424691

    Rashbastep, J.; Turro, N.J.; and Cederbaum, A.I. Increased NADPH- and NADH-dependent production of superoxide and hydroxyl radical by microsomes after chronic ethanol treatment. Archives of Biochemistry and Biophysics 300(1):401–408, 1993. PMID: 12424691

    Ross, S.A.; Halliday, M.I.; Campbell, G.C.; et al. The presence of tumour necrosis factor in CSF and plasma after severe head injury. British Journal of Neurosurgery 8(4):419–425, 1994. PMID: 7811406

    Roumen, R.M.; Hendriks, T.; van der Ven-Jongekrig, J.; et al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure. Annals of Surgery 218(6):769–776, 1993. PMID: 8257227

    Sato, H.; Tanaka, T.; and Kasai, K. Ethanol consumption impairs the hemodynamic response to hemorrhagic shock in rats. Alcohol 47(1):47–52, 2013. PMID: 23084028

    Sauaia, A.; Moore, F.A.; Moore, E.E.; et al. Early predictors of postinjury multiple organ failure. Archives of Surgery 129(1):39–45, 1994. PMID: 8279939

    Sauaia, A.; Moore, F.A.; Moore, E.E.; et al. Epidemiology of trauma deaths: A reassessment. Journal of Trauma 38(2):185–193, 1995. PMID: 7869433

    Semple, B.D.; Bye, N.; Rancan, M.; et al. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): Evidence from severe TBI patients and CCL2-/- mice. Journal of Cerebral Blood Flow and Metabolism 30(4):769–782, 2010. PMID: 20029451

    Shavelle, R.M.; Strauss, D.; Whyte, J.; et al. Long-term causes of death after traumatic brain injury. American Journal of Physical Medicine & Rehabilitation 80(7):510–516; quiz 517–519, 2001. PMID: 11421519

    Shellito, J.E., and Olariu, R. Alcohol decreases T-lymphocyte migration into lung tissue in response to pneumocystis carinii and depletes T-lymphocyte numbers in the spleens of mice. Alcoholism: Clinical and Experimental Research 22(3):658–663, 1998. PMID: 9622447

    Shohami, E.; Novikov, M.; Bass, R.; et al. Closed head injury triggers early production of TNF alpha and IL-6 by brain tissue. Journal of Cerebral Blood Flow and Metabolism 14(4):615–619, 1994. PMID: 8014208

    Skotzko, C.E.; Vrinceanu, A.; Krueger, L.; et al. Alcohol use and congestive heart failure: Incidence, importance, and approaches to improved history taking. Heart Failure Reviews 14(1):51–55, 2009. PMID: 18034302

    Souza-Smith, F.; Kurtz, K.M.; Molina, P.E.; and Breslin, J.W. Adaptation of mesenteric collecting lymphatic pump function following acute alcohol intoxication. Microcirculation 17(7):514–524, 2010. PMID: 21040117

    Spies, C.D.; Kissner, M.; Neumann, T.; et al. Elevated carbohydrate-deficient transferrin predicts prolonged intensive care unit stay in traumatized men. Alcohol and Alcoholism 33(6):661–669, 1998. PMID: 9872357

    Spies, C.D.; Neuner, B.; Neumann, T.; et al. Intercurrent complications in chronic alcoholic men admitted to the intensive care unit following trauma. Intensive Care Medicine 22(4):286–293, 1996a. PMID: 8708164

    Spies, C.D.; Nordmann, A.; Brummer, G.; et al. Intensive care unit stay is prolonged in chronic alcoholic men following tumor resection of the upper digestive tract. Acta Anaesthesiologica Scandanavica 40(6):649–656, 1996b. PMID: 8836256

    Standiford, T.J., and Danforth, J.M. Ethanol feeding inhibits proinflammatory cytokine expression from murine alveolar macrophages ex vivo. Alcoholism: Clinical and Experimental Research 21(7):1212–1217, 1997. PMID: 9347081

    Sulzer, J.K.; Whitaker, A.M.; and Molina, P.E. Hypertonic saline resuscitation enhances blood pressure recovery and decreases organ injury following hemorrhage in acute alcohol intoxicated rodents. Journal of Trauma and Acute Care Surgery 74(1):196–202, 2013. PMID: 23147176

    Szabo, G. Monocytes, alcohol use, and altered immunity. Alcoholism: Clinical and Experimental Research 22(5 Suppl.):216S–219S, 1998. PMID: 9727639

    Szmydynger-Chodobska, J.; Fox, L.M.; Lynch, K.M.; et al. Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. Journal of Neurotrauma 27(8):1449–1461, 2010. PMID: 20504162

    Tabata, T.; Tani, T.; Endo, Y.; and Hanasawa, K. Bacterial translocation and peptidoglycan translocation by acute ethanol administration. Journal of Gastroenterology 37(9):726–731, 2002. PMID: 12375146

    Taivainen, H.; Laitinen, K.; Tahtela, R.; et al. Role of plasma vasopressin in changes of water balance accompanying acute alcohol intoxication. Alcoholism: Clinical and Experimental Research 19(3):759–762, 1995. PMID: 7573805

    Tang, Y.; Forsyth, C.B.; Farhadi, A.; et al. Nitric oxide-mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage. Alcoholism: Clinical and Experimental Research 33(7):1220–1230, 2009. PMID: 19389191

    Teng, S.X., and Molina, P.E. Acute alcohol intoxication prolongs neuroinflammation without exacerbating neurobehavioral dysfunction following mild traumatic brain injury. Journal of Neurotrauma 31(4):378–386, 2014. PMID: 24050411

    Turnage, R.H.; Nwariaku, F.; Murphy, J.; et al. Mechanisms of pulmonary microvascular dysfunction during severe burn injury. World Journal of Surgery 26(7):848–853, 2002. PMID: 11965445

    Urbano-Marquez, A.; Estruch, R.; Navarro-Lopez, F.; et al. The effects of alcoholism on skeletal and cardiac muscle. New England Journal of Medicine 320(7):409–415, 1989. PMID: 2913506

    Venkatesh, B.; Hickman, I.; Nisbet, J.; et al. Changes in serum adiponectin concentrations in critical illness: A preliminary investigation. Critical Care 13(4):R105, 2009. PMID: 19570238

    Vermeij, J.D.; Aslami, H.; Fluiter, K.; et al. Traumatic brain injury in rats induces lung injury and systemic immune suppression. Journal of Neurotrauma 30(24):2073–2079, 2013. PMID: 23937270

    Wade, C.E.; Baer, L.A.; Wu, X.; et al. Severe burn and disuse in the rat independently adversely impact body composition and adipokines. Critical Care 17(5):R225, 2013. PMID: 24099533

    Wang, P.; Ba, Z.F.; Burkhardt, J.; and Chaudry, I.H. Trauma-hemorrhage and resuscitation in the mouse: Effects on cardiac output and organ blood flow. American Journal of Physiology 264(4 Pt. 2):H1166–H1173, 1993. PMID: 8476095

    Werner, C., and Engelhard, K. Pathophysiology of traumatic brain injury. British Journal of Anaesthesia 99(1):4–9, 2007. PMID: 17573392

    Whitaker, A.M.; Sulzer, J.; Walker, E.; et al. Sympathetic modulation of the host defense response to infectious challenge during recovery from hemorrhage. Neuroimmunomodulation 17(6):349–358, 2010. PMID: 20516716

    Whyte, J.; Polansky, M.; Cavallucci, C.; et al. Inattentive behavior after traumatic brain injury. Journal of the International Neuropsychological Society 2(4):274–281, 1996. PMID: 9375175

    Wichmann, M.W.; Ayala, A.; and Chaudry, I.H. Severe depression of host immune functions following closed-bone fracture, soft-tissue trauma, and hemorrhagic shock. Critical Care Medicine 26(8):1372–1378, 1998. PMID: 9710097

    Williams, F.N.; Herndon, D.N.; and Jeschke, M.G. The hypermetabolic response to burn injury and interventions to modify this response. Clinics in Plastic Surgery 36(4):583–596, 2009. PMID: 19793553

    Williams, F.N.; Herndon, D.N.; Suman, O.E.; et al. Changes in cardiac physiology after severe burn injury. Journal of Burn Care & Research 32(2):269–274, 2011. PMID: 21228708

    Willoughby, R.P.; Harris, K.A.; Carson, M.W.; et al. Intestinal mucosal permeability to 51Cr-ethylenediaminetetraacetic acid is increased after bilateral lower extremity ischemia-reperfusion in the rat. Surgery 120(3):547–553, 1996. PMID: 8784410

    Wilmore, D.W., and Aulick, L.H. Metabolic changes in burned patients. Surgical Clinics of North America 58(6):1173–1187, 1978. PMID: 32634

    Wittebole, X.; Hantson, P.; Laterre, P.F.; et al. Electrocardiographic changes after head trauma. Journal of Electrocardiology 38(1):77–81, 2005. PMID: 15660352

    Woiciechowsky, C.; Asadullah, K.; Nestler, D.; et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nature Medicine 4(7):808–813, 1998. PMID: 9662372

    Woodcock, T., and Morganti-Kossmann, M.C. The role of markers of inflammation in traumatic brain injury. Frontiers in Neurology 4:18, 2013. PMID: 23459929

    Woodroofe, M.N.; Sarna, G.S.; Wadhwa, M.; et al. Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: Evidence of a role for microglia in cytokine production. Journal of Neuroimmunology 33(3):227–236, 1991. PMID: 1874973

    Woolf, P.D.; Cox, C.; Kelly, M.; et al. Alcohol intoxication blunts sympatho-adrenal activation following brain injury. Alcoholism: Clinical and Experimental Research 14(2):205–209, 1990. PMID: 2190486

    World, M.J.; Ryle, P.R.; and Thomson, A.D. Alcoholic malnutrition and the small intestine. Alcohol and Alcoholism 20(2):89–124, 1985. PMID: 4052163

    Xu, D.Z.; Lu, Q.; and Deitch, E.A. Nitric oxide directly impairs intestinal barrier function. Shock 17(2):139–145, 2002. PMID: 11837790

    Xu, Y.X.; Ayala, A.; and Chaudry, I.H. Prolonged immunodepression after trauma and hemorrhagic shock. Journal of Trauma 44(2):335–341, 1998. PMID: 9498507

    Xu, Y.X.; Ayala, A.; Monfils, B.; et al. Mechanism of intestinal mucosal immune dysfunction following trauma-hemorrhage: Increased apoptosis associated with elevated Fas expression in Peyer’s patches. Journal of Surgical Research 70(1):55–60, 1997. PMID: 9228928

    Yo, K.; Yu, Y.M.; Zhao, G.; et al. Brown adipose tissue and its modulation by a mitochondria-targeted peptide in rat burn injury-induced hypermetabolism. American Journal of Physiology. Endocrinology and Metabolism 304(4):E331–E341, 2013. PMID: 23169784

    You, M., and Rogers, C.Q. Adiponectin: A key adipokine in alcoholic fatty liver. Experimental Biology and Medicine (Maywood) 234(8):850–859, 2009. PMID: 19491377

    Zambell, K.L.; Phelan, H.; Vande Stouwe, C.; et al. Acute alcohol intoxication during hemorrhagic shock: Impact on host defense from infection. Alcoholism: Clinical and Experimental Research 28(4):635–642, 2004. PMID: 15100616

    Zhang, P.; Bagby, G.J.; Stoltz, D.A.; et al. Granulocyte colony-stimulating factor modulates the pulmonary host response to endotoxin in the absence and presence of acute ethanol intoxication. Journal of Infectious Diseases 179(6):1441–1448, 1999. PMID: 10228066

    Zhang, Q.; Ma, B.; Fischman, A.J.; et al. Increased uncoupling protein 1 mRNA expression in mice brown adipose tissue after burn injury. Journal of Burn Care & Research 29(2):358–362, 2008. PMID: 18354294

    Zhao, Y.N.; Wang, F.; Fan, Y.X.; et al. Activated microglia are implicated in cognitive deficits, neuronal death, and successful recovery following intermittent ethanol exposure. Behavioural Brain Research 236(1):270–282, 2013. PMID: 22985845

    Ziebell, J.M., and Morganti-Kossmann, M.C. Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7(1):22–30, 2010. PMID: 20129494

    Zink, B.J.; Sheinberg, M.A.; Wang, X.; et al. Acute ethanol intoxication in a model of traumatic brain injury with hemorrhagic shock: Effects on early physiological response. Journal of Neurosurgery 89(6):983–990, 1998a. PMID: 9833825

    Zink, B.J.; Stern, S.A.; McBeth, B.D.; et al. Effects of ethanol on limited resuscitation in a model of traumatic brain injury and hemorrhagic shock. Journal of Neurosurgery 105(6):884–893, 2006. PMID: 17405260

    Zink, B.J.; Stern, S.A.; Wang, X.; and Chudnofsky, C.C. Effects of ethanol in an experimental model of combined traumatic brain injury and hemorrhagic shock. Academic Emergency Medicine 5(1):9–17, 1998b. PMID: 9444336