Neutrophil-induced lung damage after hepatic ischemia and endotoxemia.
Administration of Salmonella enteritidis endotoxin (0.5 mg ET/kg) during reperfusion (RP) after short-term hepatic ischemia (20 min) caused severe liver injury induced by Kupffer cells and neutrophils and a high mortality rate. To investigate potential lung damage in this model, lung wet-to-dry weight ratios (W/D) and broncho-alveolar lavage (BAL) protein content were determined after 4 h of reperfusion. Both parameters increased significantly during RP/ET (W/D: 4.4 +/- 0.1; BAL: 639 +/- 30 micrograms/ml) compared to controls (W/D: 3.5 +/- 0.1; BAL: 332 +/- 17). The antioxidants Trolox or tirilazad mesylate (U-74006F) effectively reduced the BAL protein increase. Alveolar macrophages were not activated; however, neutrophils isolated from the lung microvasculature of RP/ET animals showed a 300% increase of spontaneous and PMA-induced superoxide formation compared to controls (spontaneous: 1.4 +/- 0.5 nmol O2-/h/10(6) cells; PMA: 2.2 +/- 0.4). Complement factors and TNF-alpha injection induced a similar priming of vascular neutrophils for superoxide generation. Vascular neutrophil activation highly correlated with the severity of lung injury. It is concluded that neutrophils accumulated in the lung microvasculature were the major source of the oxidant stress and mainly responsible for lung injury under these conditions. Antioxidants such as tirilazad mesylate (U-74006F) may have therapeutic potential for attenuating lung injury induced by remote organ trauma and a systemic inflammatory response.
McGuire
G M
GM
Cardiovascular Pharmacology, Upjohn Company, Kalamazoo, MI 49001, USA.
Liu
P
P
Jaeschke
H
H
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004731:Endotoxins / Q000633:toxicity*; D007511:Ischemia / Q000473:pathology* / Q000503:physiopathology*; D007728:Kupffer Cells / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation; D051381:Rats; D011916:Rats, Inbred F344; D015424:Reperfusion; D012477:Salmonella enteritidis; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D004731:Endotoxins; D013481:Superoxides; D000410:Alanine Transaminase; D013755:Tetradecanoylphorbol Acetate