Distal organ insult can cause alterations in the bone marrow (BM) that may impact on the response of the distal organ to a subsequent insult. Transfer of CD11c+ cells from BM of bleomycin-treated mice exacerbates pulmonary fibrosis in recipient mice compared to those receiving cells from saline treated controls. Similarly transfer of a subpopulation of BM derived lung myeloid cells caused exacerbation of fibrosis in recipient mice. However, the nature of these alterations and the mechanism of enhancement are poorly understood. Acute exacerbation in idiopathic pulmonary fibrosis (IPF) is poorly understood with respect to pathogenic mechanism, but its resemblance to acute respiratory distress syndrome suggests involvement of the innate immune system. Based on animal model studies and the implication of innate immune system involvement in acute exacerbation in IPF, the evidence suggests that lung injury/fibrosis causes alterations in the BM that then influences the innate immune response to cause exacerbation of the response in the lung to subsequent insult. Previous and preliminary studies revealed elevated expression of the co-regulatory molecule, B7-H3 in IPF lung and detection of soluble B7-H3 in bronchoalveolar lavage fluid of IPF patients with acute exacerbation. Increased B7H3+ cells, an enhanced Th2 response and epigenetic changes in BM cells are associated with exacerbation in the bleomycin model. Thus the project's hypothesis is that initial insult to the lung caused stable alterations in BM cells that result in exacerbation of pulmonary fibrosis in response to a second insult in the same animal, or in recipients when transplanted with this altered BM. This effect is mediated by BM monocytic cells in a B7-H3 dependent manner and in part due to enhancement of lung innate immune cell recruitment and Th2 immune response. To test this hypothesis the following specific aims are proposed, 1) To analyze the effects of lung injury/fibrosis on BM cells with respect to their ability to exacerbate pulmonary fibrosis, 2) To identify the signals from the injured/fibrotic lung causing the BM alterations, 3) To elucidate the role of B7-H3 and the Th2 response in exacerbation of pulmonary fibrosis by the altered BM, and 4) To assess changes in B7-H3 expression in peripheral blood mononuclear cells and plasma from IPF patients with/without acute exacerbation. The studies will use BM chimeric and transgenic mice to evaluate BM alterations and assess their clinical relevance to exacerbation of pulmonary fibrosis by examination of human lung and blood samples from IPF patients with or without acute exacerbation.
The objective is to understand how the bone marrow is altered by lung injury and fibrosis and then influence the response of the lung to subsequent insult(s). Many chronic fibrotic diseases, such as idiopathic pulmonary fibrosis with acute exacerbation has no effective therapy. The proposed research may elucidate and identify novel therapeutic approaches.
