Inhibition of lung surfactant protein B expression during Pneumocystis carinii pneumonia in mice

The pathogenesis of Pneumocystis carinii pneumonia (PCP) suggests an import ant role for dysfunction of the pulmonary surfactant system in the hypoxemi c respiratory insufficiency associated with this infection. Surfactant prot ein B (SP-B) is a hydrophobic protein shown to be essential for normal surf actant function in vivo. Therefore, we hypothesized that the inhibition of SP-B expression occurs during PCR and we tested this hypothesis in two immu nodeficient animal models. PCP was induced in C,B-17 scid/scid mice by intr atracheal inoculation of P carinii organisms. Infected lung homogenates, ob tained 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 contro ls, the densitometric quantitation of Western blots of lung homogenates dem onstrated significant reductions in 8 kd SP-B in mice infected with P carin ii 4 weeks after inoculation (16% of the control value). Northern blot anal ysis 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 imm unosorbent assay for the SP-B level in surfactant prepared from bronchoalve olar lavage samples of infected scid mice demonstrated a significant reduct ion 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 con tent of lung homogenates from BALB/c mice depleted of CD4+ T cells and infe cted with Fl carinii was also reduced (51% of the control value). We conclu de that P. carinii induces selective inhibition of the expression of SP-B i n 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 like ly to be an important contributor to the pathogenesis of hypoxemic respirat ory failure that is observed in patients with PCP.