Parathyroid hormone-related protein, an autocrine growth inhibitor of alveolar type II cells

Parathyroid hormone-related protein (PTHRP) is an autocrine regulator of differentiation for type II pneumocytes [R. H. Hastings, D. Summers-Torres, T. C. Cheung, L. S. Ditmer, D. W. Burton, E. M. Petrin, R. G. Spragg, J. Li, and L. J. Deftos. Am. J. Physiol. 270 (Lung Cell. Mol. Physiol. 14): L353-L361, 1996]. We investigated autocrine effects on growth by decreasing endogenous PTHRP in rat type II cells. Cultured cells were incubated with antibodies against PTHRP-(1-34) (8B12) or PTHRP-(109-141) (9H7) or an irrelevant antibody (1 microg/ml) for 3 days. Conditioned media from the irrelevant antibody group contained 143 +/- 8 fg PTHRP/ 100,000 cells. The 8B12 and 9H7 reduced levels to 45 +/- 8 and 88 +/- 16 fg PTHRP/100,000 cells, respectively (n = 4 cell isolations, P < 0.05). Cells treated with the PTHRP antibodies nearly tripled in number. The irrelevant antibody had no effect on growth. Exogenous PTHRP-(1-34) (2.5 nM) blocked the growth-stimulating effect of 9H7. Instilled intratracheal 8B12 and 9H7 induced expression of proliferating cell nuclear antigen in clusters of alveolar cells in rats. Clustered cells expressed surfactant apoproteins and cytokeratin 19. These data suggest that endogenous PTHRP-(1-34) inhibits proliferation of type II cells in vivo and in vitro.