Pneumocystis pneumonia (PCP), the most common opportunistic pulmonary
infection associated with
HIV infection, is marked by impaired gas exchange and significant
hypoxemia.
Immune reconstitution disease (IRD) represents a syndrome of paradoxical
respiratory failure in patients with active or recently treated PCP subjected to immune reconstitution. To model IRD, C57BL/6 mice were selectively depleted of CD4(+) T cells using
mAb GK1.5. Following inoculation with Pneumocystis murina
cysts,
infection was allowed to progress for 2 wk, GK1.5 was withdrawn, and mice were followed for another 2 or 4 wk. Flow cytometry of spleen cells demonstrated recovery of CD4(+) cells to >65% of nondepleted controls. Lung tissue and bronchoalveolar lavage fluid harvested from IRD mice were analyzed in tandem with samples from CD4-depleted mice that manifested progressive PCP for 6 wks. Despite significantly decreased pathogen burdens, IRD mice had persistent parenchymal
lung inflammation, increased bronchoalveolar lavage fluid cellularity, markedly impaired
surfactant biophysical function, and decreased amounts of
surfactant phospholipid and
surfactant protein (SP)-B. Paradoxically, IRD mice also had substantial increases in the lung
collectin SP-D, including significant amounts of an S-nitrosylated form. By native PAGE, formation of S-nitrosylated
SP-D in vivo resulted in disruption of
SP-D multimers. Bronchoalveolar lavage fluid from IRD mice selectively enhanced macrophage chemotaxis in vitro, an effect that was blocked by ascorbate treatment. We conclude that while PCP impairs pulmonary function and produces abnormalities in
surfactant components and biophysics, these responses are exacerbated by IRD. This worsening of
pulmonary inflammation, in response to persistent Pneumocystis Ags, is mediated by recruitment of effector cells modulated by S-nitrosylated
SP-D.