Surgery (RMH) - Research Publications

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Author: Anderson, Gary × End date: 2005 × Start date: 2002 ×

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    Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity
    Beavitt, SJE ; Harder, KW ; Kemp, JM ; Jones, J ; Quilici, C ; Casagranda, F ; Lam, E ; Turner, D ; Brennan, S ; Sly, PD ; Tarlinton, DM ; Anderson, GP ; Hibbs, ML (AMER ASSOC IMMUNOLOGISTS, 2005-08-01)
    The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn-/- mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn-/- mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.
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    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.