Effects of inhaled thrombin receptor agonists in mice

Moffatt, J.D., Lever, R. and Page, C.P. (2004) Effects of inhaled thrombin receptor agonists in mice. British Journal of Pharmacology, 143 (2). pp. 269-275. 10.1038/sj.bjp.0705926.

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DOI: 10.1038/sj.bjp.0705926


Active thrombin is found in the airways of patients with a variety of inflammatory lung diseases. However, whether thrombin contributes to the pathologies of these diseases is unknown, although thrombin is a potent inflammatory mediator in other organ systems. In the present study we have assessed the acute inflammatory effect of inhaled thrombin and investigated the possible receptors mediating any effects in mice. Thrombin (200–2000 U kg−1 intranasally), induced the recruitment of a small, but significant, number of neutrophils into the airways as assessed by differential counts of cells retrieved by bronchoalveolar lavage (BAL). This small response was mimicked by peptide agonists of proteinase-activated receptor-4 (PAR4; GYPGKF, AYPGKF; 2–20 mg kg−1), but not PAR1 (SFLLRN; 2–20 mg kg−1). By contrast, trypsin (200–2000 U kg−1) caused profound inflammation and lung damage. Concentrations of tumour necrosis factor- (TNF-) were elevated in BAL fluid from thrombin-treated mice, and a TNF--neutralising antibody inhibited the influx of neutrophils in response to thrombin. Although isolated alveolar macrophages appeared to express PAR1- and PAR4-immunoreactivity, these cells failed to release TNF- above baseline levels in response to thrombin, trypsin or any of the peptide PAR agonists. Neither thrombin (2000 U kg−1) nor trypsin (200 U kg−1) modified the airway neutrophilia in response to intranasal bacterial lipopolysaccharide (LPS; 100 μg kg−1). In conclusion, exogenous thrombin has only a modest acute inflammatory action in the lung that appears to be mediated by PAR4 and involve release of TNF- from an unknown source.

Item Type:Article
Uncontrolled Keywords:Thrombin;trypsin;proteinase-activated receptor;airway;inflammation
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:3189
Journal or Publication Title:British Journal of Pharmacology
Deposited By:Library Staff
Deposited On:10 May 2012 14:47
Last Modified:10 May 2012 14:49


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