Am. J. Respir. Crit. Care Med., Volume 160, Number 4, October 1999, 1354-1360

Ethanol Ingestion Increases Activation of Matrix Metalloproteinases in Rat Lungs during Acute Endotoxemia

MANUEL LOIS, LOU ANN S. BROWN, I. MARC MOSS, JESSE ROMAN, and DAVID M. GUIDOT

Division of Pulmonary and Critical Care Medicine, Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, and Pulmonary Division, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

Previously we reported that alcohol abuse increases the incidence of the acute respiratory distress syndrome (ARDS) in septic patients, and that chronic ethanol ingestion in rats depletes alveolar epithelial glutathione and increases endotoxin-mediated lung edema. In this study we examined a potential mechanism by which ethanol-induced glutathione depletion could predispose to acute lung injury. We hypothesized that glutathione depletion activates matrix metalloproteinases (MMPs), thereby increasing degradation of the alveolar extracellular matrix (ECM) during sepsis. Ethanol-fed rats (20% vol/vol in water for 6 wk) were given endotoxin (2 mg/kg, intraperitoneally) followed 2 h later by lung isolation and ex vivo perfusion with n-formyl-methionyl-leucyl-phenylalanine (fMLP) (10⁷ M). Ethanol ingestion increased (p < 0.05) MMP-9 and MMP-2 activity, as determined by zymography, in the lung tissue and lavage fluid compared with control-fed rats, and increased (p < 0.05) levels of the 7S fragment of type IV collagen in the lung lavage fluid. Ethanol ingestion increased activation, but not production, of the MMP-9 and MMP-2 zymogens. Finally, although concomitant ingestion of N-acetylcysteine had no effect (p > 0.05) on MMP production, it increased (p > 0.05) lung glutathione levels, blocked (p < 0.05) MMP-9 and MMP-2 activation, and decreased (p < 0.05) levels of the 7S fragment of type IV collagen. We conclude that chronic ethanol ingestion, via glutathione depletion, activates MMPs during sepsis, thereby increasing degradation of the alveolar epithelial ECM. Lois M, Brown LAS, Moss IM, Roman J, Guidot DM. Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia.

This article has been cited by other articles:

				D. M. Boe, R. W. Vandivier, E. L. Burnham, and M. Moss Alcohol abuse and pulmonary disease J. Leukoc. Biol., November 1, 2009; 86(5): 1097 - 1104. [Abstract] [Full Text] [PDF]

				K. A. Radek, M. J. Ranzer, and L. A. DiPietro Brewing complications: the effect of acute ethanol exposure on wound healing J. Leukoc. Biol., November 1, 2009; 86(5): 1125 - 1134. [Abstract] [Full Text] [PDF]

				I. Vanlaere and C. Libert Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock Clin. Microbiol. Rev., April 1, 2009; 22(2): 224 - 239. [Abstract] [Full Text] [PDF]

				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]

				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. [Abstract] [Full Text] [PDF]

				P. C. Joshi, L. Applewhite, P. O. Mitchell, K. Fernainy, J. Roman, D. C. Eaton, and D. M. Guidot GM-CSF receptor expression and signaling is decreased in lungs of ethanol-fed rats Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1150 - L1158. [Abstract] [Full Text] [PDF]

				R. I. Bechara, A. Pelaez, A. Palacio, P. C. Joshi, C. M. Hart, L. A. S. Brown, R. Raynor, and D. M. Guidot Angiotensin II mediates glutathione depletion, transforming growth factor-{beta}1 expression, and epithelial barrier dysfunction in the alcoholic rat lung Am J Physiol Lung Cell Mol Physiol, September 1, 2005; 289(3): L363 - L370. [Abstract] [Full Text] [PDF]

				K. A. Radek, A. M. Matthies, A. L. Burns, S. A. Heinrich, E. J. Kovacs, and L. A. DiPietro Acute ethanol exposure impairs angiogenesis and the proliferative phase of wound healing Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1084 - H1090. [Abstract] [Full Text] [PDF]

				V. L. Kinnula, C. L. Fattman, R. J. Tan, and T. D. Oury Oxidative Stress in Pulmonary Fibrosis: A Possible Role for Redox Modulatory Therapy Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 417 - 422. [Abstract] [Full Text] [PDF]

				J. Roman, J. D. Ritzenthaler, R. Bechara, L. A. Brown, and D. Guidot Ethanol stimulates the expression of fibronectin in lung fibroblasts via kinase-dependent signals that activate CREB Am J Physiol Lung Cell Mol Physiol, May 1, 2005; 288(5): L975 - L987. [Abstract] [Full Text] [PDF]

				R. I. Bechara, L. A. S. Brown, J. Roman, P. C. Joshi, and D. M. Guidot Transforming Growth Factor {beta}1 Expression and Activation Is Increased in the Alcoholic Rat Lung Am. J. Respir. Crit. Care Med., July 15, 2004; 170(2): 188 - 194. [Abstract] [Full Text] [PDF]

				A. Pelaez, R. I. Bechara, P. C. Joshi, L. A. S. Brown, and D. M. Guidot Granulocyte/macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L106 - L111. [Abstract] [Full Text] [PDF]

				R. Rodrigo, S. Trujillo, C. Bosco, M. Orellana, L. Thielemann, and J. Araya Changes in (Na + K)-Adenosine Triphosphatase Activity and Ultrastructure of Lung and Kidney Associated With Oxidative Stress Induced by Acute Ethanol Intoxication Chest, February 1, 2002; 121(2): 589 - 596. [Abstract] [Full Text] [PDF]

				U. Michel, R. Zobotke, M. Mader, and R. Nau Regulation of Matrix Metalloproteinase Expression in Endothelial Cells by Heat-Inactivated Streptococcus pneumoniae Infect. Immun., March 1, 2001; 69(3): 1914 - 1916. [Abstract] [Full Text] [PDF]