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Direct Activation of Mouse Bronchopulmonary C‐fibers by Protease Activated Receptor‐1 (PAR1) stimulation
Author(s) -
Kwong Kevin,
Nassenstein Christina,
Undem Bradley J
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1172.12
Subject(s) - capsaicin , trpv1 , protease activated receptor 2 , receptor , thrombin , stimulation , inflammation , medicine , lung , endocrinology , ex vivo , chemistry , in vivo , protease activated receptor , immunology , biology , in vitro , transient receptor potential channel , biochemistry , platelet , enzyme linked receptor , microbiology and biotechnology
The chemical mediators most involved in bronchopulmonary C‐fiber activation at sites of airway inflammation are poorly understood. We hypothesize that stimulators of certain protease activated receptor (PARs) may be important in this regard. A single cell RT‐PCR analysis of mouse lung‐specific neurons that express the capsaicin receptor, TRPV1 (C‐fiber marker), revealed that 9 of 9 neurons also expressed PAR1 mRNA and 8 of 9 neurons express PAR3 mRNA. Neither PAR2 nor PAR4 were expressed in the C‐fiber neurons. Strong expression of all 4 PARs was found in the ganglion tissue per se (positive control). Using an ex vivo isolated lung‐nerve preparation, we found that thrombin (1 μM), which activates PAR1, PAR3 and PAR4, evoked action potential discharge in lung C‐fibers (peak frequency = 7 ± 1 Hz, n = 7). This was mimicked by TFLLR (10 μM), a selective PAR1 activating peptide, whereas SLIGRL, a selective PAR2 activating peptide, was ineffective. Consistent with the ex vivo lung preparation, TFLLR, but not SLIGRL, elicited robust inward currents (−29.8 ± 13.2 pA/pF; n = 6) in whole cell voltage clamped capsaicin‐sensitive vagal neurons. These results indicate the PAR1 is the most relevant PAR in overt activation of bronchopulmonary C fibers in mouse lungs. This has relevance to inflammatory airway disease in that PAR1 is potently activated by thrombin a peptidase known to be elevated at the site of inflammation, including allergic inflammation of the lungs. Funded by NIH.