Constitutive activation of the Src family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response

Abstract

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 sh..