Despite advances in diagnosis, highly active antiretroviral therapy, and prophylactic regimens, Pneumocystis carinii pneumonia (PCP) remains a significant cause of morbidity and mortality in HIV infected patients, as well as an important life-threatening opportunistic infection in other immunocompromised patients. Pneumocystis entry into the distal lung triggers involvement of both adaptive (cellular and humoral) and innate immune systems with specific inflammatory cascades characterized by initiation of CD4/CD8 lymphocyte responses, production of proinflammatory cytokines, recruitment of mononuclear cells, macrophage activation, and elaboration of nitric oxide and its intermediates. Two proteins isolated from lung lavage, surfactant protein (SP) -A and SP-D, members of the collectin (collagen-like lectin) family are elements of the local non-antibody mediated innate immune response. In the previous funding period, this project characterized the effects of and mechanisms by which PCP affected collectin expression in an immunocompromised mouse model of PCP. In both SP-A and SP-D null mice, PCP was associated with increased organism burden and lung injury. Building upon the previous results, the overall theme of the current proposal is to use additional novel murine models of collectin expression and in vitro systems to define the interplay between these local innate host defense molecules, Pneumocystis, innate and adaptive effector cells, and the distal pulmonary epithelia. Specifically we propose to: 1) Define the role of lung collectins (SP-A, SP-D) in clearance of Pneumocystis infection and modulation of inflammation-associated pulmonary injury using constitutively overexpressing and inducible mouse models; 2) Define cell populations and mechanisms contributing to inflammation associated surfactant dysfunction and lung injury in PCP under conditions of immune reconstitution in these murine models of collectin expression; 3) Characterize the direct effects of collectins on key effector cell responses in PCP; 4) Mechanistically define the relationship between the collectins and nitric oxide metabolism in modulating lung damage in PCP. Results from these studies are significant to enhancing our understanding of PCP pathogenesis in light of epidemiological studies linking collectin genetic polymorphisms with lung disease and recent reports of patients developing acute respiratory failure following immune reconstitution therapy after treatment for PCP. ? ? ?
| Atochina-Vasserman, Elena N (2012) S-nitrosylation of surfactant protein D as a modulator of pulmonary inflammation. Biochim Biophys Acta 1820:763-9 |
| Atochina-Vasserman, Elena N; Winkler, Carla; Abramova, Helen et al. (2011) Segmental allergen challenge alters multimeric structure and function of surfactant protein D in humans. Am J Respir Crit Care Med 183:856-64 |
| Atochina-Vasserman, Elena N; Bates, Sandra R; Zhang, Peggy et al. (2011) Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome. Am J Respir Crit Care Med 184:449-58 |
| Atochina-Vasserman, Elena N; Beers, Michael F; Gow, Andrew J (2010) Review: Chemical and structural modifications of pulmonary collectins and their functional consequences. Innate Immun 16:175-82 |
| Atochina-Vasserman, Elena N; Gow, Andrew J; Abramova, Helen et al. (2009) Immune reconstitution during Pneumocystis lung infection: disruption of surfactant component expression and function by S-nitrosylation. J Immunol 182:2277-87 |
| Guo, Chang-Jiang; Atochina-Vasserman, Elena N; Abramova, Elena et al. (2008) S-nitrosylation of surfactant protein-D controls inflammatory function. PLoS Biol 6:e266 |
| Atochina-Vasserman, Elena N; Beers, Michael F; Kadire, Helchem et al. (2007) Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice. J Immunol 179:8090-7 |
| Jain, Deepika; Atochina-Vasserman, Elena; Kadire, Helchem et al. (2007) SP-D-deficient mice are resistant to hyperoxia. Am J Physiol Lung Cell Mol Physiol 292:L861-71 |
| Zhang, Yuzhen; Rath, Nibedita; Hannenhalli, Sridhar et al. (2007) GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo. Development 134:189-98 |
| Casey, John; Kaplan, Jennifer; Atochina-Vasserman, Elena N et al. (2005) Alveolar surfactant protein D content modulates bleomycin-induced lung injury. Am J Respir Crit Care Med 172:869-77 |
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