Effects of inhaled thrombin receptor agonists in mice.
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 (PAR(4); GYPGKF, AYPGKF; 2-20 mg kg(-1)), but not PAR(1) (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-alpha (TNF-alpha) were elevated in BAL fluid from thrombin-treated mice, and a TNF-alpha-neutralising antibody inhibited the influx of neutrophils in response to thrombin. Although isolated alveolar macrophages appeared to express PAR(1)- and PAR(4)-immunoreactivity, these cells failed to release TNF-alpha 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 micrograms kg(-1)). In conclusion, exogenous thrombin has only a modest acute inflammatory action in the lung that appears to be mediated by PAR(4) and involve release of TNF-alpha from an unknown source.
Sackler Institute of Pulmonary Pharmacology, GKT School of Biomedical Sciences, Kings College London, 5th Floor Hodgkin Building, Guy's Campus, London SE1 9RT. james.moffatt@kcl.ac.uk
James D
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Rebecca
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Lever
Clive P
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D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage / Q000819:agonists / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000008:administration & dosage; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000648:ultrastructure; D044463:Receptor, PAR-1 / Q000032:analysis / Q000187:drug effects; D044464:Receptor, PAR-2 / Q000032:analysis / Q000187:drug effects; D018179:Receptors, Thrombin / Q000008:administration & dosage* / Q000819:agonists*; D013047:Specific Pathogen-Free Organisms; D013917:Thrombin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D014132:Trachea / Q000473:pathology; D014357:Trypsin / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006113:United Kingdom
C482002:GYPGKF-NH(2); D008070:Lipopolysaccharides; D009842:Oligopeptides; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D014409:Tumor Necrosis Factor-alpha; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; C082835:thrombin receptor peptide (42-47); D014357:Trypsin; D013917:Thrombin