THROMBOSPONDIN-1 IS REQUIRED FOR NORMAL MURINE PULMONARY HOMEOSTASIS AND ITS ABSENCE CAUSES PNEUMONIA

The thrombospondins are a family of extracellular calcium-binding prot eins that modulate cellular phenotype, Thrombospondin-l (TSP-L) report edly regulates cellular attachment, proliferation, migration, and diff erentiation in vitro. To explore its function in vivo, wt: have disrup ted the TSP-1 gene by homologous recombination in the mouse genome, Pl atelets from these mice are completely deficient in TSP-1 protein; how ever, thrombin-induced platelet aggregation is not diminished, TSP-l-d eficient mice display a mild and variable lordotic curvature of the sp ine that is apparent from birth, These mice also display an increase i n the number of circulating white blood cells, with monocytes and eosi nophils having the largest percent increases, The brain, heart, kidney , spleen, stomach, intestines, aorta, and Liver of TSP-1-deficient mic e showed no major abnormalities. However, consistent with high levels of expression of TSP-1 in lung, we observe abnormalities in the lungs of mice that lack the protein, Although normal at birth, histopatholog ical analysis of lungs from 4-wk-old TSP-1-deficient mice reveals exte nsive acute and organizing pneumonia, with neutrophils and macrophages , The macrophages stain for hemosiderin, indicating that diffuse alveo lar hemorrhage is occurring, At later times, the number of neutrophils decreases and a striking increase in the number of hemosiderin-contai ning macrophages is observed associated with multiple-lineage epitheli al hyperplasia and the deposition of collagen and elastin, a thickenin g and ruffling of the epithelium of the airways results From increasin g cell proliferation in TSP-1-deficient mice, These results indicate t hat TSP-I is involved in normal lung homeostasis.