Glutathione Replacement Preserves the Functional Surfactant Phospholipid Pool Size and Decreases Sepsis‐Mediated Lung Dysfunction in Ethanol‐Fed Rats

Velasquez, Alvaro; Bechara, Rabih; Lewis, James F.; Malloy, Jaret; McCaig, Lynda; Brown, Lou Ann S.; Guidot, David M.

doi:10.1111/j.1530-0277.2002.tb02663.x

Cited by 68 publications

(66 citation statements)

References 26 publications

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“…136 Chronic ethanol feeding also increased the severity of both endotoxin-induced and cecal ligation and puncture-induced lung injury. 136,137 In humans, individuals who chronically abuse alcohol but are otherwise healthy have lower levels of glutathione and a higher percentage of oxidized glutathione in bronchoalveolar lavage fluid compared with controls. 138 Patients with ARDS who abuse alcohol also have decreased levels of glutathione in bronchoalveolar lavage fluid compared with normal controls.…”

Section: Alcohol Abusementioning

confidence: 99%

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Ware¹

2006

Semin Respir Crit Care Med

433

324

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Since the adult respiratory distress syndrome was first described substantial progress has been made in understanding the pathogenesis of this complex syndrome. This review summarizes our current understanding of the pathophysiology of what is now termed the acute respiratory distress syndrome (ARDS) and its less severe form acute lung injury (ALI), with an emphasis on cellular and molecular mechanisms of injury that may represent potential therapeutic targets. Although it is difficult to synthesize all of these abnormalities into a single, unified, pathogenetic pathway, a theme that emerges repeatedly is that of imbalance, be it between pro-and anti-inflammatory cytokines, oxidants and antioxidants, procoagulants and anticoagulants, neutrophil recruitment and activation and mechanisms of neutrophil clearance, or proteases and protease inhibitors. Future therapies aimed at restoring the overall balance of cytokines, oxidants, coagulants, and proteases may ultimately be successful where therapies that target individual cytokines or other mediators have not.

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Section: Alcohol Abusementioning

confidence: 99%

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Ware¹

2006

Semin Respir Crit Care Med

433

324

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“…Adult Male Sprague-Dawley rats (initial weights 150-200 g; Charles River Laboratory, Wilmington, MA) were fed the Lieber-DeCarli liquid diet (Research Diets, New Brunswick, NJ) containing either alcohol (ethanol; 36% of total calories) or an isocaloric substitution with maltindextrin ad lib for 6 weeks as previously published (6,10,18). Zinc acetate (10, 100, or 500 mg/L) was added to the alcohol diets of some rats; each mg of zinc acetate provides approximately 0.3 mg of elemental zinc.…”

Section: Alcohol Feedingmentioning

confidence: 99%

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

Joshi¹,

Mehta²,

Jabber³

et al. 2009

Am J Respir Cell Mol Biol

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Chronic alcohol abuse impairs both alveolar epithelial and macrophage function, and renders individuals susceptible to acute lung injury, pneumonia, and other serious lung diseases. Zinc deficiency, which is known to impact both epithelial and immune cell functions, is also associated with alcohol abuse. In this study, chronic alcohol ingestion (6 wk) in rats altered expression of key zinc transporters and storage proteins in the small intestine and the lung, and decreased zinc levels in the alveolar compartment. Zinc supplementation of alveolar epithelial monolayers derived from alcohol-fed rats in vitro, or of the diets of alcohol-fed rats in vivo, restored alveolar epithelial barrier function, and these improvements were associated with salutary changes in tight junction protein expression and membrane localization. In parallel, dietary zinc supplementation increased intracellular zinc levels, GM-CSF receptor expression, and bacterial phagocytic capacity in the alveolar macrophages of alcoholfed rats. Together, these studies implicate zinc deficiency as a novel mechanism mediating alcohol-induced alveolar epithelial and macrophage dysfunction. Importantly, these findings argue that dietary supplementation can overcome alcohol-induced zinc deficiency and restore alveolar epithelial and macrophage function, and therefore could be an effective treatment for the susceptible alcoholic lung phenotype.

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“…This ethanol-induced chronic oxidant stress resulted in altered type II cell function characterized by barrier dysfunction , compromised surfactant synthesis and secretion Velasquez et al, 2002), and increased apoptosis in response to diverse pro-inflammatory mediators (Brown et al, 2001a;Brown et al, 2001b) In addition, chronic ethanol ingestion resulted in activation of lung tissue remodeling as highlighted by the increased expression at baseline of the pro-fibrotic growth factor Transforming Growth Factor-β (TGF-β) and increased release of activated TGF-β during endotoxemia (Bechara et al, 2003). Ethanol-induced oxidant stress was also associated with increased activation of Matrix Metalloproteinase (MMP) 9 and MMP-2 as well as collagen degradation during endotoxemia .…”

Section: Introductionmentioning

confidence: 99%

Alveolar type II cells from ethanol-fed rats produce a fibronectin-enriched extracellular matrix that promotes monocyte activation

Brown

Ritzenthaler

Guidot

et al. 2007

Alcohol

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Acute lung injury affects close to 200,000 people in the U.S. annually and leads to death in 40-50% of affected patients. Chronic ethanol abuse is thought to contribute to up to 40-50% of subjects who develop acute lung injury. We previously demonstrated in a rat model that chronic ethanol ingestion promoted acute lung injury and associated with chronic oxidant stress, activated matrix metalloproteinases, increased release of transforming growth factor-β, as well as increased expression and deposition of fibronectin, a matrix glycoprotein implicated in lung injury and repair. Since fibronectin can activate monocytes to increase proinflammatory cytokine expression, we hypothesized that generation of fibronectin-enriched matrices during chronic ethanol ingestion might contribute to the development of acute lung injury by stimulating unopposed inflammation. To test this hypothesis, we harvested alveolar type II cells from rats fed the Lieber DiCarli diet (6 wk; 36% of calories from ethanol). After 96 hours of culture, the matrices deposited ex vivo by the type II cells derived from ethanol-fed rats showed increased amounts of fibronectin protein as demonstrated by ELISA. When monocytic U937 cells were plated atop these matrices, there was increased expression of interleukin-1β. This stimulation was inhibited by antibodies against α5β1, a receptor that mediates many of the biological effects of fibronectin. We then tested whether antioxidants ameliorated these effects. Dietary supplements of the antioxidants N-acetylcysteine and Procysteine normalized matrix production by type II cells. Furthermore, the newly derived matrices did not stimulate interleukin-1β expression over control cells. These studies suggest that chronic ethanol exposure induces oxidant stress and activates lung tissue remodeling characterized by increased expression of fibronectin by alveolar type II cells. The newly deposited fibronectin-enriched matrices may stimulate the expression of proinflammatory cytokines in monocytic cells recruited to the lung after injury thereby explaining the priming effects of ethanol.

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Glutathione Replacement Preserves the Functional Surfactant Phospholipid Pool Size and Decreases Sepsis‐Mediated Lung Dysfunction in Ethanol‐Fed Rats

Abstract: Ethanol ingestion, via glutathione depletion, increased sepsis-mediated lung dysfunction, and these effects could contribute to the increased risk of ARDS seen in alcoholic patients.

Cited by 68 publications

References 26 publications

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Pathophysiology of Acute Lung Injury and the Acute Respiratory Distress Syndrome

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

Alveolar type II cells from ethanol-fed rats produce a fibronectin-enriched extracellular matrix that promotes monocyte activation

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