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GPCRomic Analysis of Human Lung Fibroblasts
Author(s) -
Michkov Alexander Vladimirovich,
Sriram Krishna,
Aroonsakool Nakon,
Insel Paul A
Publication year - 2016
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.30.1_supplement.969.32
Subject(s) - fibroblast , myofibroblast , g protein coupled receptor , extracellular matrix , fibrosis , lung , receptor , pulmonary fibrosis , idiopathic pulmonary fibrosis , microbiology and biotechnology , cancer research , biology , pathology , chemistry , medicine , signal transduction , in vitro , biochemistry
Many interstitial lung diseases are associated with increased numbers of fibroblast/myofibroblasts and increased deposition of extracellular matrix (ECM) proteins. Such fibroproliferative responses can lead to pulmonary fibrosis, a disease setting with very limited treatment options. Previous studies have shown that the conversion of fibroblasts into myofibroblasts and excessive deposition of ECM proteins can be regulated by the cellular level of cyclic AMP (cAMP), the synthesis of which is regulated by G‐protein signaling and G protein‐coupled receptors (GPCRs). We thus tested the hypothesis that expression of GPCRs (in particular, previously unrecognized GPCRs) by lung fibroblasts may identify novel regulators of the function of lung fibroblasts and potentially new therapeutic targets for lung fibrosis. We used real‐time PCR GPCR arrays to identify and quantify non‐chemosensory GPCRs expressed in lung fibroblasts and detected on average ~ 100 such commonly expressed receptors in low passage cultures of multiple primary isolates of human lung fibroblasts. To ascertain if the GPCR expression profile changes during the fibroblast to myofibroblast conversion, we treated fibroblasts in vitro with TGFβ1 (10 ng/ml, 48 hr). TGFβ1 treatment prominently increased the expression of pro‐fibrotic markers (e.g., collagens Iα1, Iα2, III; α‐smooth muscle actin; plasminogen activator inhibitor‐1), thus mimicking what occurs in interstitial lung diseases. GPCRomic analysis identified multiple GPCRs that were uniquely expressed in response to TGFβ1. Lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) also revealed the selective expression of a sub‐set of GPCRs. However, TGFβ1 treatment of control fibroblasts does not fully mimic the changes in GPCR expression of fibroblasts from patients with IPF. We conclude that GPCRomic analysis identifies GPCRs associated with (and that may contribute to) the fibrotic state in the lung and thus, may be novel therapeutic targets for lung fibrosis. In addition, our results imply that TGFβ1 is likely not the sole determinant of changes in GPCR expression that occur in the fibrotic state. Support or Funding Information Supported by Bristol Myers Squibb and NIH T32 HL 098062‐04