Human small airway epithelial cells (HSAEC) form the boundary between the external environmental allergens and the internal lung milieu. Mast cells are present in human lung tissue interspersed within the pulmonary epithelium, and can secrete a host of pre and newly formed mediators from their granules, which may propagate small airway inflammation. In this study, tryptase stimulation of HSAEC increased membrane - associated, calcium - independent phospholipase A₂ (iPLA₂) activity, resulting in increased arachidonic acid and prostaglandin E₂ (PGE₂) release. These responses were inhibited by pretreating HSAEC with the iPLA₂ selective inhibitor bromoenol lactone (BEL). The tryptase stimulated PGE₂ production was inhibited by treating HSAEC with the COX-1 selective inhibitor SC-560 and the non selective COX inhibitor aspirin, but not by the COX-2 selective inhibitor CAY10404 , indicating that the early release of arachidonic acid is metabolized by constitutive COX-1 to form PGE₂ in tryptase-stimulated HSAEC. Additionally platelet activating factor production and neutrophil adherence to tryptase stimulated HSAEC was also increased. This complex response can set up a cascade of inflammatory mediator production in small airways. We speculate that selective inhibition of iPLA₂ mediated phospholipid hydrolysis may prove beneficial in inflammatory airway diseases.