Abstract 1918 Poster Session IV, Tuesday, 5/4 (poster 307)

Proliferation and differentiation of type II alveolar epithelial cells are critical to the repair of the alveolar epithelium after lung injury. Keratinocyte growth factor (KGF) causes a prominent dose dependent proliferation of type II cells in the lungs of adult rats. In vitro studies of keratinocyte proliferation suggest that KGF-induced keratinocyte proliferation is mediated through autocrine production and response to transforming growth factor alpha (TGFα). We utilized transgenic mice lacking TGFα to test our hypothesis that the presence of TGFα was necessary for KGF-induced type II cell proliferation. TGFα null (-/-) mice have normal litter size, wavy hair, curly whiskers and normal lungs. KGF (10mg/kg) or an equal amount of normal saline (average 100µl) was instilled intratracheally into adult wild type (C57/b16) and TGFα -/- mice. The mice were sacrificed 72 hours later and the lungs were instillation-fixed with 10% buffered formalin, embedded in paraffin and 4µm sections were made. Immunohistochemistry using an antibody to proliferating cell nuclear antigen (PCNA) was performed on lung sections to identify proliferating cells. As expected, in the wild type mice, KGF induced robust alveolar type II cell proliferation compared with saline-treated mice. In TGFα -/- mice, contrary to our hypothesis, KGF again induced robust alveolar cell proliferation. Thus, TGFα is not necessary for KGF-induced type II cell proliferation in vivo. Further studies are necessary to determine if other epidermal growth factor receptor ligands may be sustaining as a mediator for KGF-induced proliferation.

March of Dimes (RMR)