Improved treatments for AIDS patients in the last decade have sharply reduced mortality rates due to opportun- istic diseases. However, there has been a sharp upturn in the incidence of both immune reconstitution inflam- matory syndrome (IRIS) and chronic, debilitating diseases in this patient group, including the condition that is the focus of this proposal, pulmonary hypertension. Research into IRIS has demonstrated a clear role of the immune cells that are being reconstituted in the development of pathology;whether this is true in the case of other chronic conditions such as pulmonary hypertension is not yet known. We have found that in CD4 T cell deficient mice infected with Pneumocystis murina, when CD4 cells are allowed to return, the mice gradually develop persistent pulmonary hypertension, that remains well after the disease is cleared, and most inflamma- tion has subsided. This persistent form of pulmonary hypertension is associated with perivascular remodeling, including lingering inflammatory cells, but most notably perivascular fibrosis. Because the CD4 T cell resur- gence is transient, we hypothesize that at the time of their appearance, an altered inflammatory response en- sues that causes downstream functional changes in other pulmonary cells, which in turn initiate persistent pul- monary vascular remodeling and pulmonary hypertension. The overall goal of this proposal is to identify the inflammatory cells and associated mechanisms behind Pneumocystis associated vascular remodeling, in the hope of illuminating general mechanisms of, and potential therapeutic approaches against, inflammation- related chronic pulmonary diseases.
The specific aims by which we will explore this question are as follows.
Aim 1 : Characterization of the inflammatory environment, including CD4 and CD11+ cell phenotype, associated with the onset of Pneumocystis associated vascular remodeling and pulmonary hypertension. This will be done using comparison of Pneumocystis infected mice with and without short-term depletion of CD4 cells, us- ing flow cytometric analysis of inflammatory cell subsets, ELISA analysis of pulmonary cytokines, and immuno- histochemical identification of inflammatory cells moving to areas of perivascular inflammation.
Aim 2 : In vivo determination of the necessity of specific immune system components for the initiation of vascular remodeling and pulmonary hypertension. In this aim, we will measure pulmonary hypertension as right ventricular pres- sure and right heart hypertrophy and quantify inflammation and fibrosis in lung of mice that have had important inflammatory variables isolated using genetic knockout mice or antibody-mediated depletion of the component in question.
Aim 3 : Determination of the role of inflammatory cell types in the local perivascular environment in perpetuating vascular remodeling and pulmonary hypertension. Cells suspected as necessary for the per- petuation of perivascular fibrosis will be tested in vitro for their ability to maintain fibrotic behavior in pulmonary fibroblasts. This will be followed by in vivo assessment of fibrosis and pulmonary hypertension in mice that have had this inflammatory-effector cell interaction isolated by conditional ablation or depletion.
Pulmonary hypertension is a chronic, debilitating and often fatal condition that may occur in con- junction with other lung diseases. This study looks at the immune response to a form of pneu- monia caused by the opportunistic fungi Pneumocystis in mice, as a means to understand how previous lung infections can lead to chronic pulmonary conditions such as pulmonary hyperten- sion. This type of study could also highlight the specific inflammatory processes that may be useful therapeutic targets in preventing treatable acute lung infections from becoming chronic debilitating diseases.
|Siemsen, Dan W; Dobrinen, Erin; Han, Soo et al. (2016) Vascular Dysfunction in Pneumocystis-Associated Pulmonary Hypertension Is Related to Endothelin Response and Adrenomedullin Concentration. Am J Pathol 186:259-69|
|Swain, Steve D; Siemsen, Dan W; Pullen, Rebecca R et al. (2014) CD4+ T cells and IFN-Î³ are required for the development of Pneumocystis-associated pulmonary hypertension. Am J Pathol 184:483-93|
|Swain, Steve D; Meissner, Nicole N; Siemsen, Dan W et al. (2012) Pneumocystis elicits a STAT6-dependent, strain-specific innate immune response and airway hyperresponsiveness. Am J Respir Cell Mol Biol 46:290-8|
|Swain, Steve D; Meissner, Nicole; Han, Soo et al. (2011) Pneumocystis infection in an immunocompetent host can promote collateral sensitization to respiratory antigens. Infect Immun 79:1905-14|