Proinflammatory cytokines, such as IL-1P and TNF-a, have been implicated in endotoxin shock. IV administration of these cytokines induces pulmonary edema and death, similar to the septic shock syndrome. Proinflammatory cytokines stimulate the expression of iNOS and promote inflammatory processes. Neutrophil migration in the airway is increased by chemokines, such as MIP-2, derived from alveolar macrophages. TNF-a and IL-1P stimulate chemokine-induced neutrophil chemotax-is. Neutrophils in BALF release free radicals and proteases and induce lung injury in sepsis. We successfully reduced both cytokines in lung and BALF neutrophils by inhaled L-NAME. Our study demonstrated that inhibition of NO in alveolar space decreased proinflammatory cytokines and neutrophil migration to the lung.
This might mitigate Candida-induced ALI. The inhalation of L-NAME reduced cytokine levels in serum as well as those in lung in Candida-induced ALI, although we believe that inhalation of L-NAME locally inhibited NO production in lung. This result suggests that the increase in serum cytokines was partially attributed to lung cytokines. Conversely, the reduction in lung cytokines might have induced the reduction in serum cytokines. We also demonstrated that inhalation of L-NAME did not affect candidal colony-forming units in lung, although the production of peroxyni-trite in airspaces was reduced. This finding suggests that inhalation of L-NAME locally inhibits NOS activity without worsening candidal infection in lung.
We treated mice with inhaled L-NAME before infection in this study. The effect of inhaled L-NAME after the onset of infection should be evaluated in the future studies to confirm the clinical effectiveness of this treatment.
In conclusion, our study demonstrated that NO derived from iNOS in alveolar epithelial cells and alveolar macrophages caused tissue injury in a model of Candida-induced ALI by overproduction of per-oxynitrite and proinflammatory cytokines in lung and neutrophils accumulation in lung. The inhalation of L-NAME, which locally inhibits NO production, might reduce the production of peroxynitrite and other inflammatory components in lung. These effects may improve outcome in Candida-induced ALI. We also anticipate that inhaled L-NAME might have a beneficial effect on ALI resulting from other causes associated with the overproduction of NO and peroxynitrite.