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Parenchymal Cell TNF Receptors Contribute to Inflammatory Cell Recruitment and Respiratory Failure in Pneumocystis carinii-Induced Pneumonia¹

Gloria S. Pryhuber^2,*,, Heidie L. Huyck^*, Samir Bhagwat^*, Michael A. O'Reilly^*,, Jacob N. Finkelstein^*,, Francis Gigliotti^*, and Terry W. Wright^*,

^* Department of Pediatrics, Department of Environmental Medicine, and Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642

The opportunistic organism Pneumocystis carinii (Pc) produces a life-threatening pneumonia (PcP) in patients with low CD4⁺ T cell counts. Animal models of HIV-AIDS-related PcP indicate that development of severe disease is dependent on the presence of CD8⁺ T cells and the TNF receptors (TNFR) TNFRsf1a and TNFRsf1b. To distinguish roles of parenchymal and hematopoietic cell TNF signaling in PcP-related lung injury, murine bone marrow transplant chimeras of wild-type, C57BL6/J, and TNFRsf1a/1b double-null origin were generated, CD4⁺ T cell depleted, and inoculated with Pc. As expected, C57 C57 chimeras (donor marrow recipient) developed significant disease as assessed by weight loss, impaired pulmonary function (lung resistance and dynamic lung compliance), and inflammatory cell infiltration. In contrast, TNFRsf1a/1b^–/– TNFRsf1a/1b^–/– mice were relatively mildly affected despite carrying the greatest organism burden. Mice solely lacking parenchymal TNFRs (C57 TNFRsf1a/1b^–/–) had milder disease than did C57 C57 mice. Both groups of mice with TNFR-deficient parenchymal cells had low bronchoalveolar lavage fluid total cell counts and fewer lavageable CD8⁺ T cells than did C57 C57 mice, suggesting that parenchymal TNFR signaling contributes to PcP-related immunopathology through the recruitment of damaging immune cells. Interestingly, mice with wild-type parenchymal cells but TNFRsf1a/1b^–/– hematopoietic cells (TNFRsf1a/1b^–/– C57) displayed exacerbated disease characterized by increased MCP-1 and KC production in the lung and increased macrophage and lymphocyte numbers in the lavage, indicating a dysregulated immune response. This study supports a key role of parenchymal cell TNFRs in lung injury induced by Pc and a potential protective effect of receptors on radiosensitive, bone marrow-derived cells.

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 P01HL71659, R01HL077415, R01HL064559, and P30ES01247 and the Strong Children’s Research Center.

² Address correspondence and reprint requests to Dr. Gloria S. Pryhuber, Pediatrics and Environmental Medicine, Box 850, 601 Elmwood Avenue Rochester, NY 14642. E-mail address: gloria_pryhuber{at}urmc.rochester.edu

³ Abbreviations used in this paper: Pc, Pneumocystis carinii; BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; BMT, bone marrow transplantation; KO, knockout; LDH, lactate dehydrogenase; LT, lymphotoxin; PcP, Pneumocystis carinii pneumonia; rpL32, ribosomal protein L32; sTNFR, soluble TNF receptor; tmTNF, transmembrane TNF; TNFR, TNF receptor; WT, wild type.