Am. J. Respir. Crit. Care Med., Volume 162, Number 5, November 2000, 1891-1897

Lipopolysaccharide Enhances Substance P-mediated Neutrophil Adherence to Epithelial Cells and Cytokine Release

HAN-PIN KUO, HORNG-CHYUAN LIN, KOU-HSIUNG HWANG, CHUN-HUA WANG, and LING-CHUAN LU

Department of Thoracic Medicine II, Chang Gung Memorial Hospital, Taipei, Taiwan

Lipopolysaccharide (LPS) is implicated in many respiratory tract inflammatory diseases. Tachykinins, especially substance P (SP) through the NK-1 receptor, mediate leukocyte adhesion to the endothelial or airway epithelial cells. Here we assessed the enhancement by LPS of tachykinin-mediated neutrophil adherence to alveolar epithelial cells, and associated interleukin-1 beta (IL-1) and tumor necrosis factor (TNF-) release. Neutrophil adherence to A549 epithelial cell was not increased by LPS (100 ng/ml), or SP (10¹²-10⁸ M) alone, but was significantly enhanced by their combination (LPS + SP). Neutrophil adherence to epithelial cells induced IL-1 and TNF- release from A549 cells either spontaneously or stimulated by SP or LPS. LPS + SP significantly enhanced IL-1 and TNF- release. The NK-1 receptor antagonist L-732,138 inhibited this enhancement response. Prevention of neutrophil adherence by CD11b/CD18 blocking antibody or by placing a filter on the epithelial monolayer diminished spontaneous or LPS + SP-enhanced IL-1 and TNF- release. Pretreatment with the serine protease inhibitor cocktail also inhibited LPS + SP-enhanced neutrophil adherence-dependent IL-1 and TNF- release as well as their mRNA expression. In conclusion, we have demonstrated LPS enhanced SP-mediated neutrophil adherence and associated IL-1 and TNF- release from the A549 epithelial monolayer, partly through NK-1 receptors. Neutrophil adherence to epithelial cells may release serine protease to induce IL-1 and TNF- release and their synthesis.

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