PRETREATMENT WITH INHALED NITRIC-OXIDE INHIBITS NEUTROPHIL MIGRATION AND OXIDATIVE ACTIVITY RESULTING IN ATTENUATED SEPSIS-INDUCED ACUTE LUNG INJURY

Objective: To determine if, and by what mechanisms, inhaled nitric oxi de attenuates acute lung injury in a porcine model of adult respirator y distress syndrome induced by Gram-negative sepsis. Design: Nonrandom ized, controlled study. Setting: Laboratory at a university medical ce nter. Subjects: Thirty pathogen-free Yorkshire swine (15 to 20 kg), In terventions: Four groups of swine were anesthetized, mechanically vent ilated, and studied for 5 hrs. Both control-nitric oxide and septic-ni tric oxide animals received inhaled nitric oxide at 20 parts per milli on throughout the study, Control (n = 10) and control-nitric oxide (n = 5) animals received a 1-hr infusion of sterile saline, Sepsis was in duced in septic (n = 10) and septic-nitric oxide (n = 5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. Measuremen ts and Main Results: Untreated septic animals developed a progressive decrease in Pac, that was prevented in septic-nitric oxide animals (73 +/- 4 vs. 214 +/- 23 torr [9.7 +/- 0.5 vs. 28.5 +/- 3.1 kPa], respect ively, at 5 hrs, p <.05), Untreated septic animals showed a significan t increase in bronchoalveolar lavage protein and neutrophil count at 5 hrs, compared with the baseline value, indicating acute lung injury. Septic-nitric oxide animals showed no significant increase in these pa rameters. Peripheral blood neutraphils from untreated septic animals a nd septic-nitric oxide animals exhibited significant (p < .05) up-regu lation of CD18 receptor expression and oxidant activity (10.5 +/- 0.9 and 5.0 +/- 0.9 nmol of superoxide anion/10(6) neutrophils/10 mins, re spectively) compared with both control and control nitric oxide animal s (3.0 +/- 0.6 and 2.6 +/- 0.2 nmol of superoxide anion/10(6) neutroph ils/10 mins, respectively), Also, priming for the oxidant burst at 5 h rs was decreased by 50% in septic-nitric oxide animals compared with u ntreated septic animals, Both untreated septic and septic-nitric oxide animals showed a significant increase in pulmonary arterial pressure at 30 mins (47.5 +/- 2.4 and 51.0 +/- 3.0 mm Hg, respectively), follow ed by a progressive decrease (32.8 +/- 2.6 and 31.3 +/- 5.4 mm Hg, res pectively, at 5 hrs). Both of these changes were significant (p < .05) compared with baseline values and compared with the control groups, T here was no significant difference in pulmonary arterial pressure or s ystemic arterial pressure at any time between untreated septic and sep tic-nitric oxide animals. Conclusions: These results demonstrate that inhaled nitric oxide attenuates alveolar-capillary membrane injury in this porcine model of Gram negative sepsis but does not adversely affe ct systemic hemodynamics, The data suggest that inhaled nitric oxide p reserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adhere nt neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.