In our fibrosis work, we are studying epithelial cell-fibroblast interactions and how they are influenced by matricellular proteins, eicosanoids, chemokines and inflammation. In particular, we are studying how the matricellular protein, periostin, may influence fibrogenesis and age-related susceptibility to fibrosis. We use murine models of lung fibrosis and also have several translational research projects. We are particularly interested in the role that fibrocytes may play in fibrotic lung disease and are currently generating mice in which this cell type can be conditionally depleted. Another area of interest in our fibrosis work is looking at how herpesvirus infections can augment or exacerbate fibrotic outcomes. We have demonstrated that aged, but not young mice can develop fibrosis in response to infection with murine gammaherpesvirus-68 and we are currently exploring the age-related alterations which may explain why fibrosis is associated with aging.
In our stem cell transplant work, we are interested in understanding why innate and adaptive immunity are impaired post-stem cell transplant despite hematopoietic reconstitution. We have identified epigenetic alterations which in part explain the elevation of prostaglandin E2 (PGE2) which occurs in the lung post-transplant. This increased PGE2 impairs alveolar macrophage and neutrophil function making the transplant recipients more susceptible to multiple bacterial pathogens. We study lung infection with Pseudomonas aeruginosa, Streptococcus pneumoniae and Staphylococcus aureus in these models of syngeneic and allogenic bone marrow transplantation. Our current studies in this area are focused on the role that transplant-induced deficits in autophagy and surfactant protein A play in regulating innate immune function.
Regarding adaptive immunity post-stem cell transplant, our work has shown that mice are more susceptible to murine gammaherpesvirus infections post-transplant. In allogeneic mice, the infection stimulates the graft vs. host reactions and induces severe pathology. In syngeneic transplant mice, the virus can establish latency, but the alterations in the effector T cell response (a switch from Th1 to Th17 responses) appears to drive a pneumonitis that resembles idiopathic pneumonia syndrome, a common complication of human stem cell transplants. Our current work is trying to understand how the adaptive immune response contributes to this lung pathology.
Hubbard, LLN, Wilke, CA, White, ES and B.B. Moore. 2011. Deletion of PTEN in alveolar macrophages post-BMT restores opsonized phagocytosis and host defense. Am. J. Respir. Cell Mol Biol.45(5):1050-8.. PMID: 21527775.
Domingo-Gonzalez, R., Huang SK, Laouar, Y, Wilke, CA and BB Moore, 2012. COX-2 expression is upregulated by DNA hypomethylation post-hematopoietic stem cell transplantation J. Immunol. 189(9):4528-36 PMID 23008450
Naik, PK, Bozyk, PD, Bentley, JK, Popova, AP, Birch, CM, Wilke, CA, Fry, CD, White, ES, Sisson, TH, Tayob, N, Carnemolla B., Flaherty, KR, Hershenson MB, Murray, S, Martinez, FJ , BB Moore and the COMET investigators. 2012. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 303(12)L1046-56.
Domingo-Gonzalez R, Katz S, Serezani CH, Moore TA, Levine AM, Moore BB Prostaglandin E2-induced changes in alveolar macrophage scavenger receptor profiles differentially alter phagocytosis of Pseudomonas aeruginosa and Staphylococcus aureus post-bone marrow transplant. J Immunol. 2013 Jun 1;190(11):5809-17