PMID- 15855637
OWN - NLM
STAT- MEDLINE
DCOM- 20050621
LR  - 20230513
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 166
IP  - 5
DP  - 2005 May
TI  - Absence of proteinase-activated receptor-1 signaling affords protection from 
      bleomycin-induced lung inflammation and fibrosis.
PG  - 1353-65
AB  - Activation of the coagulation cascade is commonly observed in the lungs of 
      patients with both acute and chronic inflammatory and fibrotic lung disorders, as 
      well as in animal models of these disorders. The aim of this study was to examine 
      the contribution of the major thrombin receptor, proteinase-activated receptor-1 
      (PAR-1), during the acute inflammatory and chronic fibrotic phases of lung injury 
      induced by intratracheal instillation of bleomycin in mice. Inflammatory cell 
      recruitment and increases in bronchoalveolar lavage fluid (BALF) protein were 
      attenuated by 56 +/- 10% (P < 0.05) and 53 +/- 12% (P < 0.05), respectively, in 
      PAR-1-deficient (PAR-1-/-) mice compared with wild-type (WT) mice. PAR-1-/- mice 
      were also protected from bleomycin-induced pulmonary fibrosis with total lung 
      collagen accumulation reduced by 59 +/- 5% (P < 0.05). The protection afforded by 
      PAR-1 deficiency was accompanied by significant reductions in pulmonary levels of 
      the potent PAR-1-inducible proinflammatory and profibrotic mediators, monocyte 
      chemoattractant protein-1 (MCP-1), transforming growth factor-beta-1 (TGF-beta1), 
      and connective tissue growth factor/fibroblast-inducible secreted protein-12 
      (CTGF/FISP12). In addition, PAR-1 was highly expressed in inflammatory and 
      fibroproliferative lesions in lung sections obtained from patients with fibrotic 
      lung disease. These data show for the first time that PAR-1 signaling plays a key 
      role in experimentally induced lung injury, and they further identify PAR-1 as 
      one of the critical receptors involved in orchestrating the interplay between 
      coagulation, inflammation, and remodeling in response to tissue injury.
FAU - Howell, David C J
AU  - Howell DC
AD  - Centre for Respiratory Research, University College London, The Rayne Institute, 
      5 University Street, London WC1E 6JJ, United Kingdom.
FAU - Johns, Robin H
AU  - Johns RH
FAU - Lasky, Joseph A
AU  - Lasky JA
FAU - Shan, Bin
AU  - Shan B
FAU - Scotton, Chris J
AU  - Scotton CJ
FAU - Laurent, Geoffrey J
AU  - Laurent GJ
FAU - Chambers, Rachel C
AU  - Chambers RC
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (CCN2 protein, human)
RN  - 0 (CCN2 protein, mouse)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Tgfb1 protein, mouse)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 11056-06-7 (Bleomycin)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
SB  - IM
MH  - Animals
MH  - Biopsy
MH  - *Bleomycin
MH  - Bronchoalveolar Lavage Fluid/cytology
MH  - Capillary Permeability
MH  - Cell Count
MH  - Connective Tissue Growth Factor
MH  - Cytoprotection
MH  - Humans
MH  - Immediate-Early Proteins/metabolism
MH  - Immunohistochemistry
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Lung/metabolism/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Pneumonia/*chemically induced/metabolism/pathology/physiopathology
MH  - Pulmonary Fibrosis/*chemically induced/metabolism/pathology/physiopathology
MH  - Receptor, PAR-1/deficiency/*metabolism
MH  - *Signal Transduction
MH  - Transforming Growth Factor beta/metabolism
MH  - Transforming Growth Factor beta1
PMC - PMC1606391
EDAT- 2005/04/28 09:00
MHDA- 2005/06/23 09:00
PMCR- 2005/11/01
CRDT- 2005/04/28 09:00
PHST- 2005/04/28 09:00 [pubmed]
PHST- 2005/06/23 09:00 [medline]
PHST- 2005/04/28 09:00 [entrez]
PHST- 2005/11/01 00:00 [pmc-release]
AID - S0002-9440(10)62354-1 [pii]
AID - 10.1016/S0002-9440(10)62354-1 [doi]
PST - ppublish
SO  - Am J Pathol. 2005 May;166(5):1353-65. doi: 10.1016/S0002-9440(10)62354-1.