{
  "abstract": "Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive fibrotic interstitial lung disease, with a median survival of 3–5 years post-diagnosis, characterized by excessive deposition of extra-cellular matrix (ECM). Current evidence implicates differentiated myofibroblasts, responding to aberrant TGF-β1 signalling, as primary effector cells. Classically identified by α-smooth muscle actin (α-SMA) expression, emerging evidence suggests a more complex model of distinct pathological cell sub-types. The Src-family kinases (SFKs) have been implicated in several profibrotic cellular processes, such as myofibroblast differentiation, epithelial-mesenchymal transition, and pulmonary inflammation. To define their role in fibrogenic processes in primary human lung fibroblasts (pHLFs), we conducted functional assays with small molecule inhibitors and found divergent impacts on ECM synthesis and myofibroblast differentiation. While less selective compounds showed inhibition of both processes, a novel, more selective and conformation-dependent inhibitor (NXP900) showed only inhibition of α-SMA expression, suggesting independent mechanisms for these processes. Cell-free kinome scan assays and cell-based phosphoproteomics revealed that more selective SFK inhibition does not affect TGF-β1-mediated mTOR signalling required for ECM synthesis, but does modulate cell signalling complexes associated with cytoskeletal organisation, focal adhesion, and cell-cell/substrate junctions. These results suggest specific roles for the SFKs in myofibroblast differentiation with implications for therapeutically targeting functional heterogeneity in pathological cell sub-populations in IPF.",
  "authors": [
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "M Rossanese"
    },
    {
      "affiliations": [
        "Chiesi Farmaceutici SpA, Parma, Italy"
      ],
      "name": "G Marchini"
    },
    {
      "affiliations": [
        "Chiesi Farmaceutici SpA, Parma, Italy"
      ],
      "name": "G Modafferi"
    },
    {
      "affiliations": [
        "Chiesi Farmaceutici SpA, Parma, Italy"
      ],
      "name": "B Pioselli"
    },
    {
      "affiliations": [
        "Chiesi Farmaceutici SpA, Parma, Italy"
      ],
      "name": "G Villetti"
    },
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "R Yuan"
    },
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "R Walters"
    },
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "A Kunzemann Martinez"
    },
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "M Platé"
    },
    {
      "affiliations": [
        "Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK"
      ],
      "name": "RC Chambers"
    }
  ],
  "title": "P243 Characterisation of Src-family kinase inhibitors in lung fibroblasts shows distinct signalling complexes required for matrix synthesis and differentiation",
  "uid": "f6ad2a72-0a1c-5058-a521-f692108560c7"
}