Human lung fibroblasts express proteinase-activated receptor-1 (PAR₁), PAR₂ and PAR₃, but not PAR₄. Since PAR₂ has inflammatory effects on human primary bronchial fibroblasts (HPBF), we asked: 1) whether the inflammatory mediators tumour necrosis factor- (TNF-) and lipopolysaccharide (LPS) could modify HPBF PAR expression and 2) whether modified PAR expression altered HPBF responsiveness to PAR agonists in terms of calcium signaling and cell growth. TNF- and LPS induced PAR₄ mRNA expression (RT-PCR) at 6hrs and 24hrs respectively. TNF- and LPS also upregulated PAR₂ mRNA expression with similar kinetics, but had negligible effect on PAR₁ and PAR₃. Flow cytometry for PAR₁, PAR₂ and PAR₃ also demonstrated selective PAR₂ upregulation in response to TNF- and LPS. Intracellular calcium signaling to SLIGKV-NH₂ and AYPGQV-NH₂ revealed that TNF- and LPS induced maximal responses to these PAR agonists at 24hrs and 48hrs respectively. Upregulation of PAR₂ by TNF- heightened HPBF responses to trypsin, whilst PAR₄ induction enabled cathepsin-G-mediated calcium signaling. Cathepsin-G also disarmed PAR₁ and PAR₂ in HPBF, whilst tryptase disarmed PAR2. Induction of PAR₄ also enabled thrombin to elicit a calcium signal through both PAR₁ and PAR₄ as determined by a desensitization assay. In cell growth assays the PAR₄ agonists, cathepsin-G and AYPGQV-NH₂ reduced HPBF cell number only in TNF- treated HPBF. Moreover, the mitogenic effect of thrombin (a PAR₁/PAR₄ agonist) but not the PAR₁-AP TFLLR-NH₂, was ablated in TNF- treated HPBF. These findings point to an important mechanism whereby cellular responses to thrombin and cathepsin-G can be modified during an inflammatory response.