Lavage of Leukotriene B4 Induces Lung Generation of Tumor Necrosis Factor-A and Neutrophil Diapedesis

摘要

In experimental models of acute respiratory failure, leukotriene (LT) B sub 4 is generated in the lungs, followed by a 2 to 3 hour delay before there is substantial neutrophil (PMN) accumulation and increased permeability. This study tests whether lavage of LTB sub 4 induces tumor necrosis factor (TNF) synthesis by the lungs that in turn mediates PMN diapedesis. Anesthetized rats underwent lavage of 0.1 ml LTB sub 4 (10 to the -6 power M) into a lung segment. This led to localized TNF synthesis measured in bronchoalveolar lavage fluid (BAL) with peak concentrations of 580 pg/ml after 1.5 hours and 120 pg/ml after 3 hours. These values were higher than following lavage of 0.1 ml saline, 0.7 pg/ ml and 4.3 pg/ml respectively (both p<0.05). After 30 min, the numbers were 2.2 PMN/ml while at 4 hours there was a rise to 40 PMN/ml and at 5 hours 60 PMN/ml, higher than following saline lavage (all p<0.05). Pretreatment of rats by lavage into airways of actinomycin D, 12 ng in 0.1 ml, minimized LTB sub 4 induced TNF synthesis after 1.5 and 3 hours (38 pg/ml and 51 pg/ml) as well as the delayed diapedesis after 4 hours (12 PMN/ml) (all p<0.05). Similarly, pretreatment of other rats by lavage of TNF-alpha antiserum (rabbit anti-murine), but not normal serum, limited LTB sub 4 induced diapedesis (13 PMN/ml) (p<0.05). Interestingly, administration of the protein synthesis inhibitor actinomycin D by lavage 10 min after LTB sub 4 did not prevent TNF generation after 1.5 or 3 hours (490 pg/ml and 440 pg/ml). However, this agent did limit PMN diapedesis after 4 hours (14 PMN/ml) (p<0.05). In contrast, pretreatment of rats by lavage with actinomycin D was without any effect on N-formyl-methionyl-phenylalanine (10 to the -8 power M) induced diapedesis.