INDUCTION OF FIBRINOGEN EXPRESSION IN THE LUNG EPITHELIUM DURING PNEUMOCYSTIS-CARINII PNEUMONIA

Pneumocystis carinii is an important pulmonary pathogen responsible fo r morbidity and mortality in patients with AIDS. The acute-phase respo nse (APR), the primary mechanism used by the body to restore homeostas is following infection, is characterized by increased levels of circul ating fibrinogen (FBG). Although the liver is the primary site of incr eased FBG synthesis during the APR, we unexpectedly discovered that FB G is synthesized and secreted by lung alveolar epithelial cells in vit ro during an inflammatory stimulus. Therefore, we sought to determine whether lung epithelial cells produce FBG in vivo using animal models of P. carinii pneumonia (PCP). Inflammation was noted by an influx of macrophages to P. carinii-infected alveoli. Northern hybridization rev ealed that gamma-FBG mRNA increased two- to fivefold in P. carinii-inf ected lung tissue, while RNA in situ hybridization demonstrated increa sed levels of gamma-FBG mRNA in the lung epithelium. Immunoelectron mi croscopy detected lung epithelial cell-specific production of FBG, sug gesting induction of a localized inflammatory response resembling the APR. A systemic APR was confirmed by a two- to fivefold upregulation o f the levels of hepatic gamma-FBG mRNA in animals with PCP, resulting in a corresponding increase in levels of FBG in plasma. Furthermore, i mmunoelectron microscopy revealed the presence of FBG at the junction of cell membranes of trophic forms of P. carinii organisms aggregated along the alveolar epithelium. These results implicate FBG in the path ogenesis of PCP in a manner similar to that of the adhesive glycoprote ins fibronectin and vitronectin, which are known to participate in int ra-alveolar aggregation of organisms and adherence of P. carinii to th e lung epithelium.