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 oxide attenuates acute lung injury in a porcine model of adult respiratory distress syndrome induced by Gram-negative sepsis.


METHODS
Nonrandomized, controlled study.


METHODS
Laboratory at a university medical center.


METHODS
Thirty pathogen-free Yorkshire swine (15 to 20 kg).


METHODS
Four groups of swine were anesthetized, mechanically ventilated, and studied for 5 hrs. Both control-nitric oxide and septic-nitric oxide animals received inhaled nitric oxide at 20 parts per million throughout the study. Control (n = 10) and control-nitric oxide (n = 5) animals received a 1-hr infusion of sterile saline. Sepsis was induced in septic (n = 10) and septic-nitric oxide (n = 5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa.


RESULTS
Untreated septic animals developed a progressive decrease in Pao2 that was prevented in septic-nitric oxide animals (73 +/- 4 vs. 214 +/- 23 torr [9.7 +/- 0.5 vs. 28.5 +/- 3.1 kPa], respectively, at 5 hrs, p < .05). Untreated septic animals showed a significant 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 parameters. Peripheral blood neutrophils from untreated septic animals and septic-nitric oxide animals exhibited significant (p < .05) up-regulation 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, respectively) compared with both control and control-nitric oxide animals (3.0 +/- 0.6 and 2.6 +/- 0.2 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively). Also, priming for the oxidant burst at 5 hrs was decreased by 50% in septic-nitric oxide animals compared with untreated 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), followed by a progressive decrease (32.8 +/- 2.6 and 31.3 +/- 5.4 mm Hg, respectively, at 5 hrs). Both of these changes were significant (p < .05) compared with baseline values and compared with the control groups. There was no significant difference in pulmonary arterial pressure or systemic arterial pressure at any time between untreated septic and septic-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 affect systemic hemodynamics. The data suggest that inhaled nitric oxide preserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.
Bloomfield
G L
GL
Department of Internal Medicine, Medical College of Virginia Commonwealth University, Richmond, USA.
Holloway
S
S
Ridings
P C
PC
Fisher
B J
BJ
Blocher
C R
CR
Sholley
M
M
Bunch
T
T
Sugerman
H J
HJ
Fowler
A A
AA
D000280:Administration, Inhalation; D000818:Animals; D001772:Blood Cell Count; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D016905:Gram-Negative Bacterial Infections / Q000150:complications; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000627:therapeutic use*; D011292:Premedication; D016897:Respiratory Burst / Q000187:drug effects*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications; D013552:Swine
D009569:Nitric Oxide