Surgery (RMH) - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/223

Filters

2002 - 2009 1 2010 - 2012 1
Reset filters

Settings
Statistics
Citations
Author: Anderson, Gary × Author: Bozinovski, Steven × Type: Journal Article ×

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis
    O'Donoghue, RJJ ; Knight, DA ; Richards, CD ; Prele, CM ; Lau, HL ; Jarnicki, AG ; Jones, J ; Bozinovski, S ; Vlahos, R ; Thiem, S ; McKenzie, BS ; Wang, B ; Stumbles, P ; Laurent, GJ ; McAnulty, RJ ; Rose-John, S ; Zhu, HJ ; Anderson, GP ; Ernst, MR ; Mutsaers, SE (WILEY, 2012-09)
    Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130(757F) mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130(757F);µMT(-/-) compound mutant mice, but fibrosis still occurred in their Smad3(-/-) counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis.
  • Item
    Thumbnail Image
    Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response
    Ernst, M ; Inglese, M ; Scholz, GM ; Harder, KW ; Clay, FJ ; Bozinovski, S ; Waring, P ; Darwiche, R ; Kay, T ; Sly, P ; Collins, R ; Turner, D ; Hibbs, ML ; Anderson, GP ; Dunn, AR (ROCKEFELLER UNIV PRESS, 2002-09-02)
    To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)alpha. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFalpha production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.