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The Proceedings of the American Thoracic Society 2:428-432 (2005)
© 2005 The American Thoracic Society

Alcohol, Immunosuppression, and the Lung

Kyle I. Happel and Steve Nelson

Section of Pulmonary and Critical Care Medicine, Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Correspondence and requests for reprints should be addressed to Steve Nelson, M.D., 1901 Perdido Street, Suite 3205, New Orleans, LA 70112. E-mail: Snelso1{at}lsuhsc.edu

ABSTRACT

Bacterial pneumonia is the most common cause of lower respiratory tract infection in immunocompromised populations, including the alcohol-abusing patient. Furthermore, alcoholics are frequently infected with highly virulent respiratory pathogens and consequently experience increased morbidity and mortality from bacterial pneumonia. The resulting increase in health care resource use in these patients represents a significant public health concern. Host defense mechanisms are operant from the nasopharynx to the alveolus, many of which are adversely affected by excessive alcohol intake. Although the increased risk of oropharyngeal aspiration has been recognized for centuries, only recently have detailed studies of the mechanical, innate, and adaptive immune systems identified specific mechanisms throughout the aerodigestive tract whereby ethanol exposure renders the individual more susceptible to infection. In addition to directly inhibiting the ability of resident lung immune cells to kill bacteria, excessive ethanol use suppresses the normally protective acute inflammatory response to infection, resulting in the defective recruitment of additional innate immune cells. Additionally, ethanol disrupts the intricate interface that exists between innate and adaptive pulmonary immunity, further hindering the alcoholic host's ability efficiently to eliminate invading pathogens. Whether immunomodulatory therapies, designed to augment the immune response in such patients, will be effective adjunct therapy in such patients remains to be determined. This article reviews some of the key mechanisms of pulmonary host defense that are negatively impacted in the setting of alcohol abuse.

Key Words: alcohol • pneumonia • immunosuppression • host defense • neutrophil

Alcohol is the most commonly abused substance in the United States and in most developed nations. It is estimated that 20 million Americans meet the diagnostic criteria of alcoholism, and 20 to 40% of patients admitted to hospitals serving large urban areas present with disease resulting from, or exacerbated by, alcohol abuse. The adverse health effects of this drug are wide ranging, including direct organ toxicity and predisposition to illnesses, such as neoplasm, autoimmunity, and infection. Bacterial pneumonia is perhaps the most widely recognized infectious disease associated with ethanol abuse. As early as 1785, the first surgeon general, Benjamin Rush, noted an increased susceptibility to tuberculosis and pneumonia in alcoholics. More recent studies have demonstrated that alcohol-abusing men and women suffer threefold and sevenfold greater mortality, respectively, from bacterial pneumonia compared with control patients with pneumonia (1). Similarly, a large cohort analysis identified increased hospital charges, longer lengths of stay, and increased ICU use by alcohol-abusing patients admitted for pneumonia when compared with control subjects (2). An analysis of patients with community-acquired pneumonia and septic shock found that only a history of alcohol abuse was associated with infection caused by the virulent gram-negative pathogens Pseudomonas aeruginosa and Acinetobacter species (3). To make matters worse, most patients who drink excessively also use tobacco products (4), and the detrimental effects of these substances on pulmonary defense mechanisms are additive. These findings highlight the substantial public health burden and financial impact imposed by infection resulting from excessive ethanol consumption. Accordingly, substantial efforts at both bench and bedside have increased the understanding of the precise mechanisms through which alcohol intoxication impairs the pulmonary host defense response to infection. This article reviews the current state of knowledge of alcohol's impact on the pulmonary host defense response to bacterial pneumonia.

UPPER AIRWAY DEFENSES

With the notable exceptions of aerosol-borne pathogens, such as Legionella and Mycobacterium tuberculosis, most cases of pneumonia result from the aspiration of oropharyngeal secretions containing the offending pathogen. Oral mucosal immunity is a crucial proximal location of microbial defense in the aerodigestive tract. Saliva is an important component of mucosal defense and contains bacteriostatic and cytotoxic agents, such as peroxidases, histatins, defensins, lysozyme, and lactoferrin. Immunoglobulin secretion, particularly IgA, is also an important salivary component. Chronic ethanol abuse induces sialosis, a diffuse enlargement of the major salivary glands believed to result from ethanol-induced derangements in autonomic nervous system input to these tissues, and this condition is characterized by decreased salivary production (5). In addition, the saliva of chronic alcohol consumers is defective in its acid buffering capacity, which leads to accelerated gingival disease and cavity formation (6). Such periodontal disease is accelerated by the frequent concomitant use of tobacco products by the alcohol-abusing patient, and this process provides a favorable microenvironment for the growth of anaerobic and gram-negative bacteria, particularly Klebsiella pneumoniae (7). The combination of impaired gastric acid secretion (as a result of alcohol-associated chronic atrophic gastritis) and alcohol's relaxant effect on the lower esophageal sphincter may contribute to inoculation of the mouth with these pathogenic floras.

The anatomic barriers of the epiglottis and vocal cords make aspiration into the trachea physically difficult. Strong sensory innervation pathways of the glottis and upper airways are sensitive to unwanted aspirants and initiate the cough reflex, one of the most effective means of airway clearance. Because this mechanism requires intact central nervous system input, the presence of altered mentation, as seen in pharmacologic sedation, head trauma, or alcohol intoxication, are well recognized risk factors for aspiration and the subsequent development of bacterial pneumonia (8, 9).

On entering the tracheobronchial tree, aspirated material is subject to removal from the lungs by the mucociliary escalator. The importance of an intact ciliary function in the prevention of pneumonia is evidenced by the chronic sinopulmonary infections suffered by patients with intrinsic ciliary dyskinesia conditions, such as Kartagener's syndrome. Chronic alcohol exposure has been shown to decrease ciliary beat frequency, as has the primary ethanol metabolite acetaldehyde (10, 11). Because acetaldehyde is also found in tobacco smoke, ciliary function may be particularly sensitive to combined exposure to these substances.

INNATE IMMUNITY

Pathogens that evade the proximal airway defenses gain entrance to the terminal airways and alveoli. As the predominant resident phagocyte in the airspaces, the alveolar macrophage is responsible for detecting and killing bacteria, thereby maintaining the sterility of the lower respiratory tract. Chronic alcohol ingestion impairs alveolar macrophage phagocytosis and superoxide production in response to bacterial challenge (12, 13). Alveolar macrophage recognize infectious agents by their interaction with cell surface-expressed pattern recognition receptors, including a family of receptors known as the Toll-like receptors. The ability of acute ethanol intoxication to inhibit inflammatory cytokine induction in response to a range of Toll-like receptor ligands has been reported (14). The effect of ethanol on Toll-like receptor 4 signaling, the receptor responsible for recognizing lipopolysaccharide (LPS), has been extensively studied by the authors' laboratory and by others. On LPS binding, Toll-like receptor 4 initiates a cascade of intracellular signaling events, which leads to the activation of the critical inflammatory transcription factor NF-KB. The effect of ethanol intoxication on downstream cell signaling events induced by LPS has been most studied in human monocytes, the precursors of alveolar macrophage. Acute ethanol exposure has been shown to inhibit the LPS-induced nuclear translocation of the transactivating NF-KB heterodimer p50-p65 (15). Interestingly, ethanol exposure alone increases nuclear presence of the nonactivating p50-p50 NF-KB homodimer, and intoxication in the presence of LPS stimulation does not decrease the nuclear presence of this inhibitory homodimer despite inhibiting the p50-p65 activity. Ethanol preferentially inhibits proinflammatory NF-KB signaling, thereby compromising the early response to infection.

A pivotal event in the initiation of the acute inflammatory response to infection in the lung is the induction of inflammatory cytokines. Tumor necrosis factor-{alpha} (TNF-{alpha}) is one of the best characterized early or "alarm" cytokines produced by alveolar macrophage. The importance of TNF-{alpha} in pulmonary host defense against pathogens, including Streptococcus pneumoniae, Staphylococcus aureus, Legionella pneumophila, K. pneumoniae, and M. tuberculosis, is evidenced by work demonstrating increased mortality in animals treated with antibody or soluble receptors against this factor (16). Given its central role in host defense, much work has been performed regarding modulation of TNF-{alpha} by disease states. Acute alcohol intoxication has been shown to impair the pulmonary TNF-{alpha} response to LPS challenge, although no effect on TNF-{alpha} gene up-regulation was observed, suggesting a post-transcriptional defect (17, 18). More recent work demonstrated that, by inhibiting the physical interaction between the TNF-{alpha} molecule and TNF-{alpha} converting enzyme, acute ethanol exposure prevents cleavage of TNF-{alpha} from the producing cell's surface (19), and it is believed this effect is caused in part by alcohol-mediated changes in cell membrane fluidity. The effect of chronic ethanol exposure on TNF-{alpha} release is more controversial. Although some evidence suggests chronic intoxication increases TNF-{alpha} release through augmentation of TNF-{alpha} converting enzyme activity (20) and stabilization of TNF-{alpha} mRNA (21), other work finds suppression of this cytokine resulting from chronic ingestion (22, 23).

The physiologic expression of TNF-{alpha} in the lung is central to the development of the histologic hallmark of acute inflammation, neutrophil influx. Although TNF-{alpha} is not a direct chemoattractant for neutrophils, it stimulates the release of chemokines, which orchestrate the recruitment of these cells from the vasculature. Rodent models of infection have shown that acute alcohol intoxication profoundly suppresses the lung's expression of the neutrophil chemokines MIP-2 and CINC, rodent orthologs of the human neutrophil chemokines IL-8 and Gro-{alpha}. In addition to diminished recruitment resulting from impaired chemokine expression, intrinsic defects occur in the neutrophil as a result of alcohol exposure. For example, in vivo studies have shown that neutrophil expression of the surface adhesion molecules CD11b/c and CD18 in response to LPS is suppressed by alcohol, impairing the ability of neutrophils to attach to the endothelial surface (24). Furthermore, studies of neutrophils taken from chronic alcohol abusers show these cells are hyporesponsive to chemotactic stimuli (25, 26). On reaching the infected locus, alcohol-exposed neutrophils are also less able to kill bacteria because of abnormal phagocytosis, degranulation, and superoxide generation (27–29).

In addition to these functional neutrophil defects, alcohol-abusing patients are frequently leukopenic, and they often do not mount an appropriate leukemoid reaction during infection. Although this finding has classically been attributed to hypersplenism in the chronic alcoholic, bone marrow examination of chronic alcoholics frequently shows hypocellularity and maturation arrest (30). Not surprisingly, neutropenia in the alcoholic increases mortality from pulmonary infection, particularly bacteremic pneumococcal pneumonia. Both malnutrition and direct ethanol-mediated bone marrow toxicity likely contribute to the baseline impairment in neutrophil production. In addition, the failure of alcoholics to increase neutrophil production during infection may also be attributable to a failure to initiate appropriate signaling to the bone marrow. During bacterial pneumonia, the lung expresses the hematopoietic growth factor granulocyte colony–stimulating factor (G-CSF) (31). In contrast to most cytokines, which are produced in an organ-compartmentalized fashion by the lung during infection, lung G-CSF readily exits the pulmonary tissue and enters the circulation. G-CSF serves as a means of communication between the infected lung and bone marrow. Studies of systemic infection have shown that acute alcohol inhibits the expression of G-CSF (32), and animal studies using recombinant G-CSF have shown this strategy can partially restore lung neutrophil recruitment in response to a bacterial stimulus (33). These studies prompted randomized controlled human clinical trials in which recombinant G-CSF was administered to patients with community-acquired pneumonia (34). Despite accelerated radiologic improvement and a reduction in serious complications (empyema, acute respiratory distress syndome, and disseminated intravascular coagulation), no mortality benefit was observed. Of note, only 15% of enrolled patients were alcoholics, and neutropenia was not required for study inclusion. Whether G-CSF therapy offers benefit to infected alcoholic patients, particularly those neutropenic, is unknown at this time.

ADAPTIVE IMMUNE DEFECTS

Chronic alcoholics are known to be lymphopenic, particularly those patients with alcoholic liver disease (35). Decreased thymic size and lymphocyte content have been reported in animal models of chronic intoxication (36). Furthermore, T cells from chronic alcoholics and ethanol-fed animals show a decreased response to mitogen stimulation (37) and impaired delayed-type hypersensitivity responses (38) The increased incidence of M. tuberculosis infections in the chronic alcoholic is a clear example of pulmonary infection resulting, at least partially, from the defect in cell-mediated immunity noted in these patients. Although the association of alcoholism and tuberculosis has been attributed to sociodemographic factors, several series suggest that alcohol abuse independently predisposes the individual to reactivation disease (39). Indeed, a recent report of tuberculosis risk factors in a large cross-sectional study identified alcoholism as the strongest predictor of tuberculosis (adjusted odds ratio, 7.4) (40). Animal studies of pulmonary tuberculosis have shown decreased lung CD4 and CD8 T cells and diminished proliferation in ethanol-fed mice compared with controls (41). Ethanol also markedly decreased the granulomatous response, possibly the result of impaired IFN-{gamma} secretion by T cells isolated from lungs and mediastinal lymph nodes of the alcohol-consuming mice.

Because pulmonary host defense against typical bacterial pathogens is also dependent on intact type-1 T-cell immunity (42, 43), the effects of alcohol feeding on the host response to these pathogens has been studied. Zisman and coworkers noted that pulmonary K. pneumoniae infection induces a time-dependent expression of IL-12, a critical cytokine driving T-cell IFN-{gamma} expression. In alcohol-consuming mice, both IL-12 and IFN-{gamma} expression was reduced compared with controls, effects associated with profound suppression of lung bacterial clearance (44). Instead, lungs from the ethanol-fed mice contained excessive amounts of the antiinflammatory cytokine IL-10, a response that may account for the defective Th1 response in this group. Data showing that neutralization of IL-10 improves lung and systemic clearance of K. pneumoniae suggest the importance of alcohol-induced IL-10 in suppressing an effective pulmonary host defense response (45). A role for IL-10 in the pathobiology of ethanol's immunoparalytic consequence in the lung is also supported by studies showing acute ethanol exposure induces human blood monocyte and dendritic cell IL-10 expression (46). Experimental attempts to restore lung Th1 signaling in the setting of infection and intoxication have reported that gene delivery of IFN-{gamma} to the lung can improve pulmonary host defenses against K. pneumoniae (47).

The recent discovery of the T-cell cytokine IL-17 has added to the understanding of pulmonary host defense mechanisms. IL-17 serves as a link between adaptive and innate immunity because it upregulates chemokines and cytokines promoting neutrophilic inflammation. In animal studies, inoculation with K. pneumoniae induces pulmonary IL-17 expression within 12 hours, and animals deficient in the receptor for this cytokine display an increased mortality from infection with this pathogen (48). Chronic alcohol intoxication inhibits the pulmonary IL-17 response to K. pneumoniae infection, and in vitro stimulation of T cells confirms a dose-dependent inhibition of IL-17 by ethanol (49). By pretreating animals with an adenoviral vector encoding IL-17 before K. pneumoniae inoculation, it has been shown this cytokine can improve survival of alcohol-treated animals (50). This suggests potential clinical use of IL-17 as an immunostimulatory agent.

Defects in humoral immunity have also been reported to result from alcohol abuse. In patients without liver disease, a mild decrease in circulating B cells numbers may occur, whereas a more substantial reduction is noted in those with hepatic injury (51). Despite decreases in B cell numbers, alcoholics with liver disease have increased circulating levels of nonprotective IgA, IgM, and IgG. In contrast, analysis of bronchoalveolar lavage fluid in patients with alcoholic liver disease has shown reduced total IgG and IgG1 concentrations (52). This defect was closely correlated with the development of bacterial pneumonia. Replacement immunoglobulin therapy partially restored bronchoalveolar lavage Ig levels and decreased the rate of subsequent pulmonary infection, further supporting the importance of airway antibody in host defense. Because the encapsulated organism S. pneumoniae remains the most common agent causing pneumonia in the alcohol abuser, aggressive vaccination practices should be maintained in this population. Indeed, the available evidence suggests chronic alcoholism does not impair the serologic response of the 23-valent pneumococcal polysaccharide vaccine (53). These results may reflect the fact that this preparation does not require T-cell participation for antibody production, because studies have shown T cell–independent B-cell functions are intact in animal models of chronic ethanol ingestion (54). In contrast, T cell–dependent B-cell responses are impaired by ethanol exposure (55, 56). Because protein-conjugated pneumococcal vaccines (e.g., Prevnar) require T-cell input for the robust antibody response they elicit, investigation of their effectiveness in the alcohol-abusing population is warranted before replacing traditional, nonpeptide preparations for immunization in this population.

CONCLUSIONS

Ethanol adversely affects many critical components of pulmonary host defense essential to eradicating infection and maintaining homeostasis in the host (Figure 1). The spectrum of pathogens causing pneumonia in the alcohol-abusing patient is broad and is associated with increased patient morbidity and mortality. It is incumbent on the treating physician to provide appropriate empiric therapy while aggressively pursuing microbiologic identification. Given the increased risk for the development of acute respiratory distress syndrome in the infected alcoholic (57), considerable interest exists in the development of novel immunomodulatory interventions as adjunctive therapies. The continued investigation of alcohol's effects on pulmonary immunity will facilitate the identification and application of such strategies in the immunocompromised host.



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  		Figure 1. Impairment of pulmonary host defense resulting from alcohol abuse. G-CSF = granulocyte colony–stimulating factor; IFN = interferon; IL = interleukin; PMN = polymorphonuclear leukocyte; TNF = tumor necrosis factor.

 
FOOTNOTES

Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 8, 2005; accepted in final form August 1, 2005)

REFERENCES

  1. Schmidt W, De Lint J. Causes of death of alcoholics. Q J Stud Alcohol 1972;33:171–185.[Medline]
  2. Saitz R, Ghali WA, Moskowitz MA. The impact of alcohol-related diagnoses on pneumonia outcomes. Arch Intern Med 1997;157:1446–1452.[Abstract/Free Full Text]
  3. Marik PE. The clinical features of severe community-acquired pneumonia presenting as septic shock. Norasept II Study Investigators. J Crit Care 2000;15:85–90.[CrossRef][Medline]
  4. Bien TH, Burge R. Smoking and drinking: a review of the literature. Int J Addict 1990;25:1429–1454.[Medline]
  5. Dutta SK, Dukehart M, Narang A, Latham PS. Functional and structural changes in parotid glands of alcoholic cirrhotic patients. Gastroenterology 1989;96:510–518.[Medline]
  6. Friedlander AH, Marder SR, Pisegna JR, Yagiela JA. Alcohol abuse and dependence: psychopathology, medical management and dental implications. J Am Dent Assoc 2003;134:731–740.[Abstract/Free Full Text]
  7. Fuxench-Lopez Z, Ramirez-Ronda CH. Pharyngeal flora in ambulatory alcoholic patients: prevalence of gram-negative bacilli. Arch Intern Med 1978;138:1815–1816.[Abstract/Free Full Text]
  8. Berkowitz H, Reichel J, Shim C. The effect of ethanol on the cough reflex. Clin Sci Mol Med 1973;45:527–531.[Medline]
  9. Johnson WD Jr. Impaired defense mechanisms associated with acute alcoholism. Ann N Y Acad Sci 1975;252:343–347.[Medline]
  10. Wyatt TA, Sisson JH. Chronic ethanol downregulates PKA activation and ciliary beating in bovine bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2001;281:L575–L581.[Abstract/Free Full Text]
  11. Sisson JH, Tuma DJ, Rennard SI. Acetaldehyde-mediated cilia dysfunction in bovine bronchial epithelial cells. Am J Physiol 1991;260:L29–L36.
  12. Greenberg SS, Zhao X, Hua L, Wang JF, Nelson S, Ouyang J. Ethanol inhibits lung clearance of Pseudomonas aeruginosa by a neutrophil and nitric oxide-dependent mechanism, in vivo. Alcohol Clin Exp Res 1999;23:735–744.[CrossRef][Medline]
  13. Brown LA, Harris FL, Ping XD, Gauthier TW. Chronic ethanol ingestion and the risk of acute lung injury: a role for glutathione availability? Alcohol 2004;33:191–197.[CrossRef][Medline]
  14. Pruett SB, Zheng Q, Fan R, Matthews K, Schwab C. Ethanol suppresses cytokine responses induced through Toll-like receptors as well as innate resistance to Escherichia coli in a mouse model for binge drinking. Alcohol 2004;33:147–155.[Medline]
  15. Mandrekar P, Dolganiuc A, Bellerose G, Kodys K, Romics L, Nizamani R, Szabo G. Acute alcohol inhibits the induction of nuclear regulatory factor kappa B activation through CD14/toll-like receptor 4, interleukin-1, and tumor necrosis factor receptors: a common mechanism independent of inhibitory kappa B alpha degradation? Alcohol Clin Exp Res 2002;26:1609–1614.[CrossRef][Medline]
  16. Nelson S, Bagby GJ, Mason CM, Summer W. Cytokines and the antibacterial defenses of the lung. In: Nelson S, Martin T, editors. Cytokines in pulmonary disease. New York: Marcel Dekker;2000. pp. 131–148.
  17. Nelson S, Bagby G, Summer WR. Alcohol suppresses lipopolysaccharide-induced tumor necrosis factor activity in serum and lung. Life Sci 1989;44:673–676.[CrossRef][Medline]
  18. Kolls JK, Xie J, Lei D, Greenberg S, Summer WR, Nelson S. Differential effects of in vivo ethanol on LPS-induced TNF and nitric oxide production in the lung. Am J Physiol 1995;268:L991–L998.
  19. Zhao XJ, Marrero L, Song K, Oliver P, Chin SY, Simon H, Schurr JR, Zhang Z, Thoppil D, Lee S, et al. Acute alcohol inhibits TNF-alpha processing in human monocytes by inhibiting TNF/TNF-alpha-converting enzyme interactions in the cell membrane. J Immunol 2003;170:2923–2931.[Abstract/Free Full Text]
  20. Zhang Z, Bagby GJ, Stoltz D, Oliver P, Schwarzenberger PO, Kolls JK. Prolonged ethanol treatment enhances lipopolysaccharide/phorbol myristate acetate-induced tumor necrosis factor-alpha production in human monocytic cells. Alcohol Clin Exp Res 2001;25:444–449.[CrossRef][Medline]
  21. Kishore R, McMullen MR, Nagy LE. Stabilization of tumor necrosis factor alpha mRNA by chronic ethanol: role of A + U-rich elements and p38 mitogen-activated protein kinase signaling pathway. J Biol Chem 2001;276:41930–41937.[Abstract/Free Full Text]
  22. Standiford TJ, Danforth JM. Ethanol feeding inhibits proinflammatory cytokine expression from murine alveolar macrophages ex vivo. Alcohol Clin Exp Res 1997;21:1212–1217.[CrossRef][Medline]
  23. Omidvari K, Casey R, Nelson S, Olariu R, Shellito JE. Alveolar macrophage release of tumor necrosis factor-alpha in chronic alcoholics without liver disease. Alcohol Clin Exp Res 1998;22:567–572.[CrossRef][Medline]
  24. Zhang P, Bagby GJ, Xie M, Stoltz DA, Summer WR, Nelson S. Acute ethanol intoxication inhibits neutrophil beta2-integrin expression in rats during endotoxemia. Alcohol Clin Exp Res 1998;22:135–141.[CrossRef][Medline]
  25. Gluckman SJ, Dvorak VC, MacGregor RR. Host defenses during prolonged alcohol consumption in a controlled environment. Arch Intern Med 1977;137:1539–1543.[Abstract/Free Full Text]
  26. MacGregor RR, Gluckman SJ, Senior JR. Granulocyte function and levels of immunoglobulins and complement in patients admitted for withdrawal from alcohol. J Infect Dis 1978;138:747–755.[Medline]
  27. Zhang P, Bagby GJ, Stoltz DA, Summer WR, Nelson S. Granulocyte colony-stimulating factor modulates the pulmonary host response to endotoxin in the absence and presence of acute ethanol intoxication. J Infect Dis 1999;179:1441–1448.[CrossRef][Medline]
  28. Tamura DY, Moore EE, Partrick DA, Johnson JL, Offner PJ, Harbeck RJ, Silliman CC. Clinically relevant concentrations of ethanol attenuate primed neutrophil bactericidal activity. J Trauma 1998;44:320–324.[Medline]
  29. Sachs CW, Christensen RH, Pratt PC, Lynn WS. Neutrophil elastase activity and superoxide production are diminished in neutrophils of alcoholics. Am Rev Respir Dis 1990;141:1249–1255.[Medline]
  30. Ballard HS. Hematological complications of alcoholism. Alcohol Clin Exp Res 1989;13:706–720.[CrossRef][Medline]
  31. Tazi A, Nioche S, Chastre J, Smiejan JM, Hance AJ. Spontaneous release of granulocyte colony-stimulating factor (G-CSF) by alveolar macrophages in the course of bacterial pneumonia and sarcoidosis: endotoxin-dependent and endotoxin-independent G-CSF release by cells recovered by bronchoalveolar lavage. Am J Respir Cell Mol Biol 1991;4:140–147.[Medline]
  32. Bagby GJ, Zhang P, Stoltz DA, Nelson S. Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication. Alcohol Clin Exp Res 1998;22:1740–1745.[CrossRef][Medline]
  33. Nelson S, Summer W, Bagby G, Nakamura C, Stewart L, Lipscomb G, Andresen J. Granulocyte colony-stimulating factor enhances pulmonary host defenses in normal and ethanol-treated rats. J Infect Dis 1991;164:901–906.[Medline]
  34. Nelson S, Belknap SM, Carlson RW, Dale D, DeBoisblanc B, Farkas S, Fotheringham N, Ho H, Marrie T, Movahhed H, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J Infect Dis 1998;178:1075–1080.[Medline]
  35. Bernstein IM, Webster KH, Williams RC Jr, Strickland RG. Reduction in circulating T lymphocytes in alcoholic liver disease. Lancet 1974;2:488–490.[CrossRef][Medline]
  36. Saad AJ, Jerrells TR. Flow cytometric and immunohistochemical evaluation of ethanol-induced changes in splenic and thymic lymphoid cell populations. Alcohol Clin Exp Res 1991;15:796–803.[CrossRef][Medline]
  37. Spinozzi F, Bertotto A, Rondoni F, Gerli R, Scalise F, Grignani F. T-lymphocyte activation pathways in alcoholic liver disease. Immunology 1991;73:140–146.[Medline]
  38. Lundy J, Raaf JH, Deakins S, Wanebo HJ, Jacobs DA, Lee T, Jacobowitz D, Spear C, Oettgen HF. The acute and chronic effects of alcohol on the human immune system. Surg Gynecol Obstet 1975;141:212–218.[Medline]
  39. Olin JS, Grzybowski S. Tuberculosis and alcoholism. Can Med Assoc J 1966;94:999–1001.[Medline]
  40. Altet-Gomez MN, Alcaide J, Godoy P, Romero MA, Hernandez R. I. Clinical and epidemiological aspects of smoking and tuberculosis: a study of 13,038 cases. Int J Tuberc Lung Dis 2005;9:430–436.[Medline]
  41. Mason CM, Dobard E, Zhang P, Nelson S. Alcohol exacerbates murine pulmonary tuberculosis. Infect Immun 2004;72:2556–2563.[Abstract/Free Full Text]
  42. Moore TA, Perry ML, Getsoian AG, Newstead MW, Standiford TJ. Divergent role of gamma interferon in a murine model of pulmonary versus systemic Klebsiella pneumoniae infection. Infect Immun 2002;70:6310–6318.
  43. Greenberger MJ, Kunkel SL, Strieter RM, Lukacs NW, Bramson J, Gauldie J, Graham FL, Hitt M, Danforth JM, Standiford TJ. IL-12 gene therapy protects mice in lethal Klebsiella pneumonia. J Immunol 1996;157:3006–3012.[Abstract]
  44. Zisman DA, Strieter RM, Kunkel SL, Tsai WC, Wilkowski JM, Bucknell KA, Standiford TJ. Ethanol feeding impairs innate immunity and alters the expression of Th1- and Th2-phenotype cytokines in murine Klebsiella pneumonia. Alcohol Clin Exp Res 1998;22:621–627.[CrossRef][Medline]
  45. Greenberger MJ, Strieter RM, Kunkel SL, Danforth JM, Goodman RE, Standiford TJ. Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol 1995;155:722–729.[Abstract]
  46. Szabo G, Mandrekar P, Dolganiuc A, Catalano D, Kodys K. Reduced alloreactive T-cell activation after alcohol intake is due to impaired monocyte accessory cell function and correlates with elevated IL-10, IL-13, and decreased IFNgamma levels. Alcohol Clin Exp Res 2001;25:1766–1772.[CrossRef][Medline]
  47. Kolls JK, Lei D, Stoltz D, Zhang P, Schwarzenberger PO, Ye P, Bagby G, Summer WR, Shellito JE, Nelson S. Adenoviral-mediated interferon-gamma gene therapy augments pulmonary host defense of ethanol-treated rats. Alcohol Clin Exp Res 1998;22:157–162.[CrossRef][Medline]
  48. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 2001;194:519–527.[Abstract/Free Full Text]
  49. Shellito JE, Quan ZM, Ye P, Ruan S, Shean MK, Kolls J. Effect of alcohol consumption on host release of interleukin-17 during pulmonary infection with Klebsiella pneumoniae. Alcohol Clin Exp Re. 2001;25:872–881.
  50. Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 2001;25:335–340.[Abstract/Free Full Text]
  51. Cook RT, Waldschmidt TJ, Cook BL, Labrecque DR, McLatchie K. Loss of the CD5+ and CD45RAhi B cell subsets in alcoholics. Clin Exp Immunol 1996;103:304–310.[CrossRef][Medline]
  52. Spinozzi F, Cimignoli E, Gerli R, Agea E, Bertotto A, Rondoni F, Grignani F. IgG subclass deficiency and sinopulmonary bacterial infections in patients with alcoholic liver disease. Arch Intern Med 1992;152:99–104.
  53. McMahon BJ, Parkinson AJ, Bulkow L, Davidson M, Wainwright K, Wolfe P, Schiffman GS. Immunogenicity of the 23-valent pneumococcal polysaccharide vaccine in Alaska Native chronic alcoholics compared with nonalcoholic Native and non-Native controls. Am J Med 1993;95:589–594.[CrossRef][Medline]
  54. Jerrells TR, Smith W, Eckardt MJ. Murine model of ethanol-induced immunosuppression. Alcohol Clin Exp Res 1990;14:546–550.[CrossRef][Medline]
  55. Chang MP, Wang Q, Norman DC. Diminished proliferation of B blast cell in response to cytokines in ethanol-consuming mice. Immunopharmacol Immunotoxicol 2002;24:69–82.[CrossRef][Medline]
  56. Szabo G. Consequences of alcohol consumption on host defence. Alcohol Alcohol 1999;34:830–841.[Abstract/Free Full Text]
  57. Moss M, Bucher B, Moore FA, Moore EE, Parsons PE. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 1996;275:50–54.[Abstract/Free Full Text]



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D. K. Meyerholz, M. Edsen-Moore, J. McGill, R. A. Coleman, R. T. Cook, and K. L. Legge
Chronic Alcohol Consumption Increases the Severity of Murine Influenza Virus Infections
J. Immunol., July 1, 2008; 181(1): 641 - 648.
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 Am. J. Respir. Crit. Care Med.Home page
P. O. Mitchell and D. M. Guidot
Alcohol Ingestion by Donors Amplifies Experimental Airway Disease after Heterotopic Transplantation
Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1161 - 1168.
[Abstract] [Full Text] [PDF]

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M. K. Elliott, J. H. Sisson, and T. A. Wyatt
Effects of Cigarette Smoke and Alcohol on Ciliated Tracheal Epithelium and Inflammatory Cell Recruitment
Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 452 - 459.
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P. C. Joshi and D. M. Guidot
The alcoholic lung: epidemiology, pathophysiology, and potential therapies
Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L813 - L823.
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G. Szabo, A. Dolganiuc, Q. Dai, and S. B. Pruett
TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects
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[Abstract] [Full Text] [PDF]

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