| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854; and
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, and Veterans Affairs Medical Center, Ann Arbor, MI 48109
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 Following inoculation with Pneumocystis murina cysts, infection was allowed to progress for 2 wk, GK1.5 was withdrawn, and mice were followed for another 2 or 4 wk.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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 HL64520 (to M.F.B.) and R01 HL083482 (to J.M.B.).
2 Address correspondence and reprint requests to Dr. Michael F. Beers and Dr. Elena N. Atochina-Vasserman, Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, H410F Hill Pavilion, 380 S. University Avenue, Philadelphia, PA 19104. E-mail addresses: mfbeers{at}mail.med.upenn.edu and atochina{at}mail.med.upenn.edu
3 Abbreviations used in this paper: PCP, Pneumocystis pneumonia; SNO, S-nitrosothiol; BALF, bronchoalveolar lavage fluid; iNOS, inducible nitric oxide synthase; IRD, immune reconstitution disease; LA, large aggregate; SA, small aggregate; SP-A, pulmonary surfactant protein A (35 kDa); SP-B, pulmonary surfactant protein B (9 kDa); SP-C, pulmonary surfactant protein C (3.7 kDa); SP-D, pulmonary surfactant protein D (43 kDa).
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
