Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia.
Pneumocystis carinii is an important pulmonary pathogen responsible for morbidity and mortality in patients with AIDS. The acute-phase response (APR), the primary mechanism used by the body to restore homeostasis following infection, is characterized by increased levels of circulating fibrinogen (FBG). Although the liver is the primary site of increased FBG synthesis during the APR, we unexpectedly discovered that FBG is synthesized and secreted by lung alveolar epithelial cells in vitro 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 revealed that gamma-FBG mRNA increased two- to fivefold in P. carinii-infected lung tissue, while RNA in situ hybridization demonstrated increased levels of gamma-FBG mRNA in the lung epithelium. Immunoelectron microscopy detected lung epithelial cell-specific production of FBG, suggesting induction of a localized inflammatory response resembling the APR. A systemic APR was confirmed by a two- to fivefold upregulation of the levels of hepatic gamma-FBG mRNA in animals with PCP, resulting in a corresponding increase in levels of FBG in plasma. Furthermore, immunoelectron 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 pathogenesis of PCP in a manner similar to that of the adhesive glycoproteins fibronectin and vitronectin, which are known to participate in intra-alveolar aggregation of organisms and adherence of P. carinii to the lung epithelium.
Departments of Medicine-Vascular Medicine Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. pj_simpsonhaidaris@urmc.rochester.edu
P J
PJ
Simpson-Haidaris
M A
MA
Courtney
T W
TW
Wright
R
R
Goss
A
A
Harmsen
F
F
Gigliotti
D000210:Acute-Phase Reaction; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001483:Base Sequence; D018076:DNA, Complementary; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism; D005289:Ferrets; D005340:Fibrinogen / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D011020:Pneumonia, Pneumocystis / Q000378:metabolism* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D005340:Fibrinogen