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Guidot March 31 2011

Guidot March 31 2011 - The Alcoholic Lung The A...

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Unformatted text preview: The Alcoholic Lung: The A Physician’s Perspective David M. Guidot, MD Professor of Medicine Division of Pulmonary, Allergy, & Critical Care An illustrative case? An • 57 year old man with a long history of alcohol abuse abuse • presents with acute abdominal pain presents • exploratory laparotomy reveals focal small bowel ischemia/infarction and active peritonitis ischemia/infarction • post-op he develops sepsis syndrome and ARDS post-op He has a prolonged course in the MICU but fortunately does not develop multiple organ failure. He is extubated after one month and eventually returns home after an extensive course of physical therapy. course Meanwhile . . . Meanwhile • 53 year old man with type II diabetes and hypertension is admitted with abdominal pain and fever fever • exploratory laparotomy shows a perforated appendix and a peri-appendiceal abscess is drained appendix • admission blood cultures grow E. coli E. • he develops sepsis physiology and fluid overload secondary to liberal IV fluid treatment but this resolves rapidly with diuretics resolves On post-operative day #4 he is extubated and transfers to the surgical ward. The next day he has a room air oximetry of 93%. He is discharged on post-operative day # 8 and makes an uneventful recovery. recovery. Whether or not a patient with sepsis, trauma, pancreatitis etc. develops ARDS may not be a matter of chance. ARDS “The Role of Chronic Alcohol Abuse in the The Development of Acute Respiratory Distress Syndrome in Adults” Distress Marc Moss, MD; Becki Bucher, PhD; Frederick Moore, Marc MD; Ernest Moore, MD; Polly Parsons, MD. JAMA 1996 MD; 351 critically ill patients at risk for ARDS followed prospectively 351 50 40 ARDS ARDS incidence 30 20 (%) 10 0 non-alcoholic alcoholic The association between alcohol abuse and The pneumonia has been recognized for centuries pneumonia Benjamin Rush Benjamin 1745-1813 Sir William Osler 1849-1919 How do we know what we know? what Theodoric of York, Medieval Barber Theodoric Epidemiology Epidemiology Pathophysiology We needed an animal model model Fernando Holguin, my first research fellow Fernando Alvaro Velasquez Alvaro Chronic ethanol ingestion in rats renders Chronic the lung susceptible to injury the + endotoxin-mediated edematous injury in endotoxin-mediated lungs perfused ex vivo (Fernando, JCI, ex 1998) 1998) sepsis-mediated lung injury in vivo (Alvaro, sepsis-mediated in Alcoholism: Clin Exp Res, 2002) Alcoholism: The “glutathione story” The Glutathione (GSH) is a critical antioxidant in the alveolar space antioxidant Really, really good! GSH H2O2 R-OOH g GSSG lut ath ion ep Bad! ero xid hydrogen peroxide ase H2O lipid hydroperoxides R-OH Good! Chronic ethanol ingestion in rats severely decreased alveolar epithelial lining fluid GSH lining p < 0.05 400 alveolar alveolar epithelial lining fluid fluid glutathione (µ M) 300 200 100 0 Treatment none Holguin et. al., JCI, 1998 ethanol What about humans? What Chronic alcoholics have decreased levels of glutathione in their lung lavage fluid their 600 alveolar alveolar epithelial lining fluid GSH GSH (µ M) 75 I’m about here 500 400 25 300 75 200 100 0 25 controls AJRCCM, 2000 alcoholics In the laboratory . . . , In Glutathione replacement: • restores alveolar epithelial function restores • restores alveolar macrophage function restores • decreases sepsis-mediated acute lung injury decreases . . . , however, for a variety of reasons I do not believe that acute glutathione replacement will prevent lung injury in critically ill alcoholic patients. low glutathione in the lung reflects oxidative damage and dysfunction that is not immediately reversible immediately “it’s more like driving your car it’s without oil than running out of gas” From Ware and Matthay. NEJM 342(18): 1334-1349, 2000. Ware From Ware and Matthay. NEJM 342(18): 1334-1349, 2000. Ware Manuel Lois joins the lab Manuel Chronic ethanol ingestion alters both components of the dynamic alveolar epithelial barrier AJP: Lung Cellular and Molecular Physiology (July 2000) AJP: The “alcoholic lung” cannot weather a The storm storm sepsis sepsis pumps already pumps working near maximum capacity capacity leaky epithelium Rabih Bechara Rabih Chronic ethanol ingestion increases the Chronic expression of TGFβ 1 in the alveolar expression macrophages and type II cells macrophages type II cells cells macrophages macrophages Chronic alcohol abuse Chronic ↑ angiotensin II angiotensin ↑ chronic O2* stress chronic TGFβ 1 ↑ TGFβ 1 expression TGF ↑ TGFβ 1 release and TGF activation activation acute O2* stress Chronic alcohol abuse Chronic ↑ angiotensin II angiotensin Can be targeted with drugs Can such as ACE inhibitors or angiotensin II receptor blockers blockers ↑ chronic O2* stress chronic Can be targeted with Can glutathione precursors such as S-adenosyl methionine methionine TGFβ 1 ↑ TGFβ 1 expression TGF The “alcoholic lung” The ↓ glutathione glutathione ↑ TGFβ TGF ↓ epithelial barrier function epithelial Epidemiology Epidemiology Pathophysiology How do we define alcohol abuse? How It is a ‘behavioral’ and/or ‘consequential’ It definition: definition: • CAGE questionnaire CAGE • Short Michigan Alcohol Survey (SMAST) Short • Alcohol Use Disorder Identification Test (AUDIT) (AUDIT) It is not defined by quantity of alcohol It consumed, or the presence of end-organ damage (such as cirrhosis). (such The magnitude of the problem The • In 2002, there were ~ 12,000 deaths in the U.S. directly attributable to alcohol-mediated liver disease. (National Center for Health Statistics) (National • In 1993, there were ~ 18,000 deaths in the U.S. attributed to alcohol-related traffic accidents. (MMWR Report) Report) • In 2002, there were ~ 3,000 deaths in the U.S. attributed to acute pancreatitis, although not all cases were directly attributable to alcohol abuse. (National Center for Health Statistics) Statistics) • We estimate that there are ~ 15,000-25,000 deaths per year in the U.S. from alcohol-mediated respiratory failure. the Which of these people is an alcoholic? Which We all recognize that he is at increased risk of pneumonia and ARDS, pneumonia but are we aware that but she is at increased risk as well? as Epidemiology Epidemiology Prevention Treatment Pathophysiology GM-CSF and Zinc GM-CSF Andres Pelaez Andres Pratibha Joshi Pratibha Ashish Mehta Chronic alcohol ingestion decreases alveolar macrophage function macrophage Alveolar Macrophage Bacteria Decreased Phagocytosis GM-CSF-mediated signaling is important for macrophage function macrophage Alveolar Macrophage Bacteria Phagocytosis GM-CSF binds to cell surface receptors GM-CSF Y Y Y Y Y Y Y Alveolar Alveolar Epithelium Epithelium Y Y Y Y Y Y Alveolar Alveolar Macrophage Macrophage GM-CSF Alcohol decreases GM-CSF receptor expression expression Y Y Y Y Down-regulation of Down-regulation receptors receptors Y Y Y Alveolar Alveolar Epithelium Epithelium Y Y Y Y Y Y Alveolar Alveolar Macrophage Macrophage GM-CSF Zinc Biology Zinc Zn Liver Absorbed in Absorbed small intestine small Zinc Homeostasis Zinc ZIP ZnT Zn MT ZnT MT Metallothionein ZIP Zinc supplementation restores GM-CSF receptor expression receptor Y Y Y Y Y Y Y Alveolar Alveolar Epithelium Epithelium Zinc Supplementation Y Y Y Y Y Y Alveolar Alveolar Macrophage Macrophage GM-CSF Dietary zinc supplementation in alcohol-fed rats improves alveolar macrophage phaocytosis improves 600 * 500 * * 400 Phagocytic 300 index 200 100 0 Dietary Zn acetate (mg/L) 0 10 100 500 (Joshi et. al., AJRCMB) (Joshi How do we know what we know? what Theodoric of York, Medieval Barber Theodoric The Emory Alcohol and Lung Biology Center is an integrated, multidisciplinary group focused on translational research translational We recognize that in order to We “translate”, you have to speak both languages languages We can go from here . . . We or from here . . . to here . . . relevant animal models that to relevant enable us to examine the independent effects of alcohol on the lung and other organs on to here . . . immunohistochemistry of the to immunohistochemistry alcohol-fed rat lung showing increased expression of TGFβ 1 increased alcohol alcohol to here . . . alcohol + GM-CSF GM-CSF treatment increases GM-CSF expression of its own receptor in the alcoholic macrophage the With the goal of using our research findings to With preserve or even restore health in individuals who suffer from alcohol abuse (and its . . . and then back again. consequences). and consequences). It is time to consider a new treatment approach in chronic alcohol abuse approach Maintenance therapy: • addiction treatment/abstinence programs addiction • ACE inhibitor, dietary zinc supplements • glutathione supplements such as NAC or SAM glutathione sepsis, trauma Acute interventions: • glutathione glutathione • GM-CSF GM-CSF ...
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