Involvement of thromboxane A2 in bronchial hyperresponsiveness but not lung inflammation induced by bacterial lipopolysaccharide in guinea pigs.
We examined both a possible association of bronchial hyperresponsiveness with lung inflammatory responses and the role of thromboxane (Tx) A2 in these responses after lipopolysaccharide (LPS) exposure in guinea pigs treated with metyrapone, a cortisol synthesis inhibitor. The increase in bronchial responsiveness to i.v. acetylcholine was transient, with a peak at 2 h after LPS exposure, which was associated with increases in TxB2 and tumor necrosis factor in bronchoalveolar lavage (BAL) fluid. However, the levels of 6-keto-prostaglandin (PG) F1 alpha, interleukin-1 and interleukin-6 in BAL fluid, and the influx of leukocytes in airway and pulmonary edema were not associated with bronchial hyperresponsiveness. Oral administration of S-1452, a selective TxA2 receptor antagonist, markedly suppressed bronchial hyperresponsiveness without affecting cellular responses, pulmonary edema and production of PGs and cytokines. These findings suggest that LPS-induced bronchial hyperresponsiveness is dependent on secondarily generated TxA2, which appears to be independent of lung inflammation.
Arimura
A
A
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Asanuma
F
F
Yagi
H
H
Kurosawa
A
A
Harada
M
M
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006168:Guinea Pigs; D007375:Interleukin-1 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008797:Metyrapone / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D011453:Prostaglandins / Q000096:biosynthesis; D011654:Pulmonary Edema / Q000139:chemically induced; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001643:Bridged Bicyclo Compounds; D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; C056566:S 145; D013928:Thromboxane A2; D008797:Metyrapone