The EGF ligands bind differentially to the ErbBs and initiate hom

The EGF ligands bind differentially towards the ErbBs and initiate homodimeric or heterodimeric receptor dimerization to cause tyrosine phosphorylation of intracellular receptor residues and downstream cell signaling via mitogen activated protein kinases, phosphatidylinositol three kinase, and transcription factors which includes STAT 3. The EGFR ligands are significant to epithelial repair following injury, and as illustrated in Figure three, certain EGFR ligands also play necessary roles inside the pathogenesis of pulmonary fibrosis by pro moting mesenchymal cell survival and proliferation. Hence, their role has been described as both protec tive against acute lung injury or profibrogenic, depend ing on the context of lung injury or the inciting agent. For instance, the administration of recombinant amphir egulin attenuates bleomycin induced pulmonary fibrosis in mice, suggesting a protective function for this EGFR ligand.
TGF a plays a protective function against nickel induced lung injury by escalating topical Hedgehog inhibitor levels of surfac tant proteins. Yet, the targeted overexpression of TGF a to distal airway epithelium or conditional expression of TGF a in mouse lung benefits in pulmon ary fibrosis. Alternatively, TGF a deficiency pro tects mice from bleomycin induced fibrosis. As a result, it really is most likely that TGF a exerts its beneficial effects by means of promoting epithelial repair and improved surfactant production, whereas its profibrogenic activity is most likely linked to its activity as a potent mitogen for mesenchymal cells. Additionally, it seems that quick term TGF a expression stimulates epithelial cell development and repair throughout acute lung injury, whereas long term TGF a expression leads to excessive mesenchymal cell growth and stimulation of matrix deposition and fibro sis.
HB EGF is also a potentially necessary mitogen for mesenchymal cells. Human airway epithelial cells and human lung fibroblasts each make HB find more info EGF in response to vanadium induced oxidative anxiety. These studies working with human cells indicated that paracrine signaling between the airway epithelium and underlying mesenchymal cells as well as autocrine production of HB EGF by mesenchymal cells might be important to airway fibrogenesis brought on by metal injury. Treatment with all the EGFR kinase inhibitor AG1478 prior to the instillation of vanadium oxide ameliorates pulmonary fibrosis. Also, AG1478 attenuates upregulation of procollagen expression in tracheal explants from rats exposed to cigarette smoke. Consequently, several lines of evidence indicate that signaling via EGFR is important to both mesenchymal cell proliferation and matrix production in the course of fibrogenesis. Nevertheless, unlike PDGF members of the family, that are primarily mesenchy mal cell survival components, EGF ligands are also necessary survival elements for the lung epithelium and hence appear to function in each repair following injury at the same time as disease progression.

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