My research focuses on the role of a secreted glycoprotein, milk fat globule epidermal growth factor-like-8 (Mfge8), in two processes with relevant roles in lung disease: collagen metabolism as it relates to pulmonary fibrosis and apoptotic cell clearance as it relates to asthma and inflammation in the lung.

To investigate the role of Mfge8 in tissue fibrosis, I have challenged Mfge8 deficient mice with intratracheal bleomycin and found that Mfge8 deficiency results in an exaggerated fibrotic response to bleomycin as compared with wild type control mice. Though my previous work identified a critical role for Mfge8 in apoptotic cell clearance and regulation of inflammation in the involuting mammary gland, neither of these processes are perturbed in the lungs of Mfge8 deficient mice after bleomycin treatment. My current data identifies a novel role for Mfge8 in mediating collagen endocytosis by macrophages both in vitro and in vivo. These findings support a model by which secreted Mfge8 targets collagen for removal from the extracellular matrix. Mfge8 deficiency results in more severe pulmonary fibrosis secondary to impaired remodeling of fibrotic tissue. Consistent with this hypothesis is a relative increase in vivo in total lung collagen protein in Mfge8 deficient mice after bleomycin treatment without a concurrent increase in procollagen transcript production suggesting impaired collagen degradation with intact collagen production. I am currently in the process of identifying which domain of Mfge8 mediates collagen binding/endocytosis.

These data raise several interesting questions. First, the therapeutic potential of a molecule that can augment resorbtion of scar tissue in established pulmonary fibrosis will be of significant scientific and therapeutic interest. The majority of current work on pulmonary fibrosis is focused on inhibiting pathways that lead to excessive collagen production. From the therapeutic viewpoint, this approach relies on identification and intervention in patients early on in the disease process who are likely to develop progressive disease. Identification of a molecule, and ultimately a family of molecules, that can be administered to patients with established pulmonary fibrosis will impact a larger patient population with limited therapeutic options. I plan to investigate both the therapeutic efficacy of Mfge8 in reducing established fibrosis and to identify other molecules that are critical in this process both in the lung and other tissues that are prone to fibrosis. I am also interested in further evaluating the role of macrophages as key mediators of scar remodeling. I have also established that Mfge8 mediated collagen endocytosis is independent of RGD binding integrins, the main receptors currently identified for this molecule. I plan to identify the cellular receptor for Mfge8 important in tissue fibrosis and identify other ligands for this receptor. Identifying the molecular pathways that mediate remodeling of tissue fibrosis will be one of the long-term focuses of my research program.

The second major area of interest is the role of apoptotic cell clearance in modulating the severity of inflammation and allergic disease in the lung. Mfge8 mediates phosphatidylserine-dependent phagocytosis of apoptotic cells and Mfge8 deficiency leads to chronic autoimmune disease. Mfge8 mediates many of the immune-modulating effects of GM-CSF and may regulate the production of adaptive regulatory T cells through its induction of interleukin 10 and TGF-beta. I have found that mice deficient in Mfge8 develop significantly worse asthma as measured by airway hyperresponsiveness in both an acute and chronic ovalbumin asthma model. The phenotypic difference is more pronounced in the chronic allergen challenge model where it is associated with a profound difference in interstitial inflammation. I am in the process of evaluating differences in apoptotic cell clearance, T cell subsets, cytokine production, and collagen deposition in these mice. I am currently exploring the hypothesis that Mfge8 mediated apoptotic cell clearance of inflammatory cells after allergen challenge provides an inhibitory pathway that serves to dampen the asthmatic response. My data thus far suggests that there is a failure of clearance of apoptotic inflammatory cells in Mfge8 deficient mice. I am also exploring the therapeutic potential of Mfge8 in preventing the development of, reducing the frequency of acute episodes, and reducing the duration of an acute episode of asthma.