Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury.
BACKGROUND
The major hemodynamic feature of endotoxin (ETX)-induced acute lung injury is pulmonary hypertension secondary to increased pulmonary vascular resistance. Endotoxin causes dysfunction of pulmonary vasorelaxation, which is associated with increased lung neutrophil accumulation. We hypothesized that neutrophils mediate the dysfunction of cGMP-mediated pulmonary vasorelaxation in acute lung injury. In a rat model of ETX-induced lung injury, our purpose was to determine the effect of neutrophil depletion on the following mechanisms of pulmonary vasomotor control: endothelium-dependent cGMP-mediated relaxation (response to acetylcholine) and endothelium-independent relaxation (response to sodium nitroprusside).


METHODS
Rats were studied 6 hours after ETX (20 mg/kg). Neutropenia (< 75 neutrophils/microL) was induced with anti-neutrophil serum 24 hours before ETX. Saline injected rats were controls. Dose-response curves to acetylcholine and sodium nitroprusside were generated in isolated pulmonary artery rings preconstricted with phenylephrine (n = 10 rings/5 rats per group). Lungs were harvested (n = 4 rats/group) and lung neutrophil accumulation was assessed with a myeloperoxidase assay.


RESULTS
Endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was dysfunctional in ETX-induced ALI. Neutrophil depletion prevented lung neutrophil accumulation and attenuated pulmonary vasomotor dysfunction after endotoxin.


CONCLUSIONS
These data suggest that neutrophils contribute to pulmonary endothelium and smooth muscle dysfunction in acute lung injury induced by endotoxemia.
Sheridan
B C
BC
Department of Surgery, University of Colorado, Denver, USA.
McIntyre
R C
RC
Moore
E E
EE
Meldrum
D R
DR
Agrafojo
J
J
Fullerton
D A
DA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins; D006152:Cyclic GMP / Q000494:pharmacology; D004731:Endotoxins; D007958:Leukocyte Count; D008297:Male; D009503:Neutropenia / Q000503:physiopathology*; D009504:Neutrophils; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000302:isolation & purification; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium; D014655:Vascular Resistance / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology*
D001427:Bacterial Toxins; D004731:Endotoxins; C027952:salmonella toxin; D009599:Nitroprusside; D009195:Peroxidase; D006152:Cyclic GMP; D000109:Acetylcholine