Inhibition of lung surfactant protein B expression during Pneumocystis carinii pneumonia in mice.
The pathogenesis of Pneumocystis carinii pneumonia (PCP) suggests an important role for dysfunction of the pulmonary surfactant system in the hypoxemic respiratory insufficiency associated with this infection. Surfactant protein B (SP-B) is a hydrophobic protein shown to be essential for normal surfactant function in vivo. Therefore, we hypothesized that the inhibition of SP-B expression occurs during PCP, and we tested this hypothesis in two immunodeficient animal models. PCP was induced in C.B-17 scid/scid mice by intratracheal inoculation of P. carinii organisms. Infected lung homogenates, obtained at time points up to 6 weeks after inoculation, were analyzed for SP-B and mRNA content. When a comparison was made with uninfected scid controls, the densitometric quantitation of Western blots of lung homogenates demonstrated significant reductions in 8 kd SP-B in mice infected with P. carinii 4 weeks after inoculation (16% of the control value). Northern blot analysis showed a concomitant decrease in SP-B mRNA to 24% of the control level. The decrease in SP-B and mRNA levels in lung homogenates of infected mice was reflected in lower SP-B levels in the surfactant. An enzyme-linked immunosorbent assay for the SP-B level in surfactant prepared from bronchoalveolar lavage samples of infected scid mice demonstrated a significant reduction in alveolar SP-B content (45% of the control value). In contrast to the results with SP-B, neither the SP-A protein content nor the mRNA level was significantly altered by PCP infection. To confirm these observations, SP-B expression was studied in an additional animal model of PCP. The SP-B content of lung homogenates from BALB/c mice depleted of CD4+ T cells and infected with P. carinii was also reduced (51% of the control value). We conclude that P. carinii induces selective inhibition of the expression of SP-B in two mouse models of PCP and that this down-regulation is mediated at the level of mRNA expression. Therefore, an acquired deficiency of SP-B is likely to be an important contributor to the pathogenesis of hypoxemic respiratory failure that is observed in patients with PCP.
Beers
M F
MF
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6068, USA.
Atochina
E N
EN
Preston
A M
AM
Beck
J M
JM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011020:Pneumonia, Pneumocystis / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D011510:Proteolipids / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012131:Respiratory Insufficiency / Q000209:etiology
D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger