Liver-lung interactions during E. coli endotoxemia. TNF-alpha:leukotriene axis.
The liver modulates host responses to endotoxemia by production and clearance of tumor necrosis factor alpha (TNF-alpha) and eicosanoid lipoxygenation products. Reductions in liver blood flow (QL) are common during endotoxemia, but it is unknown whether the kinetics of TNF-alpha and leukotrienes (LTs) are thereby altered to amplify lung inflammation. To test this hypothesis, reductions in QL were modeled by an end-to-side portacaval shunt (PCS) in Sprague-Dawley rats. Conscious animals received 2.5 mg/kg of intravenous E. coli lipopolysaccharide (LPS) serotype 055:B5 (PCS + LPS; n = 17) or saline (n = 5). Responses were compared with those in sham-operated rats (sham + LPS; n = 13) and NSS-challenged control rats (n = 5). Cardiopulmonary changes, serum TNF-alpha, and formed elements were determined at t = 0, 1.5, 3.5, and 24 h, when organ wet/dry ratios (W/D) were measured with TNF-alpha, LTB4, and polymorphonuclear neutrophils (PMN) in bronchoalveolar lavage fluid (BALF). In PCS + LPS rats, mortality was 59% and serum TNF-alpha peaked at 1.5 h (2,784 +/- 658 U/ml, mean +/- SEM) coincident with the onset of hypotension. Despite equivalent endotoxemia and liver- and lung-associated TNF-alpha in sham + LPS rats at 1.5 h, peak serum TNF-alpha was 38% less and mortality was 15% (p < 0.05). Cardiac, hepatic, and cecal W/D were likewise increased in PCS + LPS versus sham + LPS rats, as were BALF PMNs (p < 0.05). In parallel studies, the disappearance kinetics of infused rTNF-alpha were not altered in nonendotoxemic PCS animals, implicating enhanced lung uptake of LPS and systemic export of TNF-alpha in PCS + LPS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Matuschak
G M
GM
Department of Internal Medicine, Saint Louis University School of Medicine, Missouri.
Mattingly
M E
ME
Tredway
T L
TL
Lechner
A J
AJ
D000818:Animals; D016470:Bacteremia / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004049:Diethylcarbamazine / Q000494:pharmacology; D004731:Endotoxins / Q000097:blood; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000032:analysis / Q000502:physiology; D008099:Liver / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D009504:Neutrophils / Q000737:chemistry; D009929:Organ Size / Q000187:drug effects; D011167:Portacaval Shunt, Surgical; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology; D002722:Chlorobenzenes
D004049:Diethylcarbamazine; D004731:Endotoxins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes