Abrogation of thrombin-induced increase in pulmonary microvascular permeability in PAR-1 knockout mice

We investigated the function of proteinase-activated receptor-1 (PAR-1) in the regulation of pulmonary microvascular permeability in response to thrombin challenge using PAR-1 knockout mice (−/−). Lungs were isolated and perfused with albumin (5 g/100 ml)-Krebs solution at constant flow (2 ml/min). Lung wet weight and pulmonary artery pressure (Ppa) were continuously monitored. We determined the capillary filtration coefficient (Kfc) and 125I-labeled albumin (BSA) permeability-surface area product (PS) to assess changes in pulmonary microvessel permeability to liquid and albumin, respectively. Normal and PAR-1-null lung preparations received in the perfusate: 1) thrombin or 2) selective PAR-1 agonist peptide (TFLLRNPNDK-NH2). In control PAR-1 (+/+) mouse lungs, 125I-albumin PS and Kfc were significantly increased over baseline (by ∼7- and 1.5-fold, respectively) within 20 min of α-thrombin (100 nM) challenge. PAR-1 agonist peptide (5 μM) gave similar results, whereas control peptide (5 μM; FTLLRNPNDK-NH2)...