Induction of Fibrinogen Expression in the Lung Epithelium duringPneumocystis cariniiPneumonia

Abstract

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. cariniipneumonia (PCP). Inflammation was noted by an influx of macrophages to P. carinii-infected alveoli. Northern hybridization revealed that γ-FBG mRNA increased two- to fivefold in P. carinii-infected lung tissue, while RNA in situ hybridization demonstrated increased levels of γ-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 γ-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 ofP. carinii to the lung epithelium.

H7N9 and Other Pathogenic Avian Influenza Viruses Elicit a Three-Pronged Transcriptomic Signature That Is Reminiscent of 1918 Influenza Virus and Is Associated with Lethal Outcome in Mice

“…Depressed coagulation factor transcription in the lungs of mice infected with pathogenic avian viruses may offer insight into these observations, especially since this has also been observed in mice infected with highly pathogenic H1N1 strains, such as the 1918 virus (27). Though the liver is the primary site of fibrinogen synthesis, lung epithelial cells also produce fibrinogen in response to inflammation, IL-6 treatment, and infection with severe acute respiratory syndrome coronavirus (SARS-CoV) or Pneumocystis jirovecii (58)(59)(60)(61). H7N9 infection does not affect coagulation factor transcription in airway epithelial cells (20), suggesting that this signature is produced by other cells such as alveolar macrophages, which produce coagulation factors in response to stimulation (62).…”

Author's reply to Weijers et al. “Fibrin β15–42 domain is cryptic in intact fibrinogen: comment on the study by A. Sahni et al.”

“…31,32 Extrahepatic expression of fibrinogen occurs in vivo, as demonstrated in animal models of Pneumocystis carinii pneumonia, and by gene expression profiling of biopsy samples from patients with lung or breast cancer. [33][34][35][36][37][38][39] The functional significance of fibrinogen expression by extrahepatic epithelium is likely influenced more by the cellular context in which the fibrinogen is found rather than by its overall plasma concentration.…”

Fibrinogen is localized on dark zone follicular dendritic cells in vivo and enhances the proliferation and survival of a centroblastic cell line in vitro

“…The localization of fibrinogen on FDC in the DZ could therefore be important in situ to create a microenvironment, where the concentration of fibrinogen is sufficiently high to maintain the proliferation and survival of the DZ B cell blasts. It is important that such concentrations of fibrinogen could be expected locally within the secondary lymphoid organs, as the fibrinogen concentration in rat and human plasma averages 3 mg/ml [36,44,55], and up to 0.5 mg/ml fibrinogen has been detected in rabbit and rat lymph [45,46]. Finally, it was not possible to show that the effects of fibrinogen on L3055 cells were modified in the presence of the FDC-1 cell line.…”

“…Fibrinogen is produced mainly by hepatocytes in the liver, although mRNA transcripts have also been detected in other tissues such as the lung, ovary, and bone marrow under normal and pathological conditions [35][36][37]. Therefore, we next determined whether fibrinogen was expressed in situ within the secondary lymphoid organs.…”