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

Chen, Hsing I

In addition to the experimental studies and clinical investigations on the pathogenesis of ALI/ARDS, our laboratory has carried out several experimentations on the therapeutic regimen for this serious disorder. In conscious rats, regular exercise training attenuates septic responses such as systemic hypotension, increases in plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, creatinine, amylase, lipase, asparate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactic dehydrogenase, TNF α, and IL β . Exercise training also abrogates the cardiac, hepatic and pulmonary injuries caused by endotoxemia. [124] Insulin exerts anti-inflammatory effects on the ALI and associated biochemical changes following intravenous administration of lipopolysaccharide (LPS). [127] Propofol (2,6-diisopropylphenol) has been commonly used for sedation in critically ill patients. [128] This anesthetic has rapid onset, short duration and rapid elimination. [129] Propofol protects the anesthetized rats from ALI caused by endotoxin. [65] In conscious rats, oleic acid results in sepsis-like responses including ALI, inflammatory reactions and increased in neutrophil-derived factors (neutrophil elastase, myeloperoxidase and malondialdehyde), nitrate/nitrite, methyl guanidine, inflammatory cytokines. It depresses the sodium-and potassium-activated ATPase, but upregulates the iNOS mRNA expression. Pretreatment and posttreatment with propofol alleviates or reverses the oleic acid-induced lung pathology and associated biochemical changes. [54] Pentobarbital, an anesthetic agent commonly used in experimental studies and a hypnotic for patients improves the pulmonary and other organ functions following LPS administration. It also increases the survival rate. [15] A later study by Yang et al. [130] further revealed that pentobarbital suppressed the expression of tumor necrosis factor α , which might result from decrease in the activities of nuclear factor-κβ and activator protein 1 and reduction in expression of P38 mitogen-activated protein kinase. In vivo examination of cytotoxic effects of LPS disclosed that LPS caused multiple organ dysfunctions. These changes were attenuated by pentobarbital. Pentobarbital also reduced the cell aptosis caused by deforoxamine-induced hypoxia. Nicotinamide or niacinamide (compound of soluble B complex) abrogates the ALI caused by ischemic/reperfusion or endotoxin by mechanism through inhibition on poly (ADP-ribose) synthase or permerase cytoxic enzyme and subsequent suppression of iNOS, NO, free radicals and proinflammatory cytokines with restoration of adenosine triphosphate ATP. [48, 53] N-acetylcysteine, an antioxidant and cytoprotective agent with scavenging action on reactive oxygen species and inhibitory effects on proinflammatory cytokines ameliorated organ dysfunctions due to sepsis in conscious rats. [131, 132] In a similar endotoxin-induced ALI model, we found that N-acetylcysteine improved the LPS-induced systemic hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in lung weight changes, exhaled NO and lung pathology. In addition, N-acetylcysteine diminished the LPS-induced increases in nitrate/nitrite, TNF α , and IL β [64] In isolated lungs, N-acetylcysteine attenuated the ALI caused by phorbol myristate acetate. [86] In a recent study, we reported that posttreatment with N-acetylcysteine prevented the ALI caused by fat embolism. [50] Our series of expe