Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations

Chen, Hsing I

rvations that NO production through the iNOS may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (LPS, endotoxin) provoked systemic hypotension, endothelial damage and ALI accompanied by increased plasma nitrate/nitrite and expression of iNOS mRNA, TNF α and IL-1 β . The LPS-induced changes were abolished by nonspecific and specific iNOS inhibitors such as N ω -monomethyl-L-arginine (L-NMMA), L-NAME, aminoguanine and dexamethosone. [35] This study suggested that NO/iNOS, TNF α and IL-1 β were involved in the endotoxemia-induced ALI. Generation of NO from the activated neutrophil caused alveolar injury from smoke inhalation. [36] Experiments in many laboratories using specific iNOS inhibitors and/or iNOS-knockout animals have supported the contention that NO/iNOS is responsible for the oxidative stress and endothelial damage in the ARDS/ALI caused by endotoxin, ozone exposure, carrageenan treatment, hypoxia, acute hyperoxia, bleomaycin administration, acid aspiration and other causes. [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] Our laboratory further provided evidence to suggest that the NO/iNOS system is involved in the pathogenesis of ALI caused by air embolism, [47] fat embolism, [48] [49] [50] ischemia/ reperfusion, [51] [52] [53] oleic acid [54] and phorbol myristate acetate. [55] In these recent studies, various insults caused increase in nitrate/nitrite in plasma or lung perfusate, upregulation of iNOS mRNA in lung parenchyma accompanied with elevation of proinflammatory cytokines such as TNF α , IL-1 β and IL-6. Lin et al. [56] have suggested that an increase in iNOS mRNA triggers the release of proinflammatory cytokines in septic and conscious rats. The inflammatory responses results in multiple organ damage including ALI. Inhibition of iNOS with S-methylisothiourea (SMT) or L-Nil attenuated the inflammatory changes, release of NO and cytokines and prevented the organ dysfunction and ALI. [52]