02 May 2003
Med Sci Monit 2003; 9(1): 35- :: ID: 15098
The acute respiratory distress syndrome (ARDS) is a severe form of pulmonary inflammation arising as a complication of local (pneumonia, smoke inhalation, aspiration), or systemic (sepsis, trauma, burn injury and pancreatitis) inflammatory processes. The main features of ARDS are diffuse alveolar damage, high permeabiltity pulmonary edema, inflammatory cell infiltration, and loss of surfactant production, resulting in severe disturbances of lung mechanics and gas exchanges. Recent investigations support the concept that activation of PARP, secondary to locally produced oxygen- and nitrogen-derived free radicals and oxidants, may represent a key mechanism of pulmonary inflammation and lung injury in experimental ARDS. In vitro, PARP is activated in response to oxidant-driven DNA damage in respiratory epithelial cells, leading to bioenergetic failure and necrotic cell death . PARP activation also plays a role in the loss of surfactant production by type II pneumocytes exposed to hydrogen peroxide . In vivo, the PARP inhibitor 5-aminoisoquinoline reduced the degree of lung injury and pulmonary neutrophil infiltration in rats challenged by intra-thoracic zymosan-activated plasma, via a mechanism involving a reduced expression of endothelial P-selectin and ICAM-1 . In a murine model of ARDS triggered by the intratracheal instillation of endotoxin, PARP suppression (either by genetic deletion or pharmacological inhibition with PJ-34) markedly reduced the local release of pro-inflammatory cytokines (TNFa, IL-1b and IL-6), and chemokines (MIP-1a and MIP-2), resulting in a lesser degree of neutrophil accumulation and pulmonary edema, as well as in an improved histological status . Thus, oxidant-triggered activation of PARP mediates lung epithelial cell damage and dysfunction, and also represents a central mechanism regulating leukocyte trafficking and the expression of pro-inflammatory mediators within the injured lung. These observations suggest that the pharmacological inhibition of PARP might be useful in clinical conditions associated with overwhelming lung inflammation such as ARDS. References: 1.Nanavaty UB et al: Exp Lung Res, 2002; 28: 591-607 2.Hudak BB et al: Am J Physiol, 1995; 269: L59-64 3.Cuzzocrea S et al: Biochem Pharmacol, 2002; 63: 293-304 4.Liaudet L et al: Am J Respir Crit Care Med, 2002; 165: 372-7
Keywords: Lung, ARDS, PARP, neutrophil
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