{"id":180,"date":"2015-04-08T19:25:05","date_gmt":"2015-04-08T19:25:05","guid":{"rendered":"http:\/\/depts.washington.edu\/cfrtc\/?p=180"},"modified":"2017-06-01T17:43:57","modified_gmt":"2017-06-01T17:43:57","slug":"pilot-8-investigating-the-effects-of-cftr-correction-on-myeloid-cell-function","status":"publish","type":"post","link":"https:\/\/depts.washington.edu\/cfrtc\/pilot-8-investigating-the-effects-of-cftr-correction-on-myeloid-cell-function\/","title":{"rendered":"Pilot 8 – Manicone"},"content":{"rendered":"

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Pilot 8: Functional consequences and signaling pathways of macrophage repolarization<\/h1>\n

P.I.: Anne Manicone, MD<\/a>
\nAssistant Professor of Medicine
\nCenter for Lung Biology
\nPulmonary and Critical Care Medicine<\/p>\n

Pulmonary macrophages have dichotomous roles in promoting and resolving inflammatory responses in the lung; and they do this in part by their ability to adopt different activation or polarized states. In an “M1” polarized state, they participate in clearance of bacteria and secretion of pro-inflammatory cytokines\/chemokines. They can also adopt an “M2” polarized state, and this activation state is important in promoting wound resolution, including clearance of debris and apoptotic neutrophils. A balance of M1 and M2 polarization is likely necessary for a normal inflammatory response to infection; and an imbalance in these activation states may contribute to lung disease. The functional role of M1 and M2 cells in regulating chronic inflammatory diseases is far from clear, and potentially an imbalance of M1\/M2 function may contribute to lung disease. In fact, an increase in M2 cells has been reported in CF airways and is associated with worse lung function.1 Particularly in CF, macrophage polarization may be altered by chronic exposure to apoptotic neutrophils (a stimulus for M2 polarization) and to bacteria (a stimulus for M1 polarization). In addition, other factors specific to or associated with CF, such as a role of CFTR or hyperglycemia in macrophage plasticity and M2 repolarization remain unexplored.<\/p>\n

My laboratory is interested in the functional roles of M2 cells in acute and chronic lung inflammation and the signaling pathways involved in promoting M2 programming. Our murine studies reveal the following: (1) alveolar macrophage repolarize from M1 to M2 in vivo during the resolution of P. aeruginosa pneumonia, (2) repolarized alveolar macrophages contribute to lung injury resolution in an acute model (not shown), and (3) greater M2 responses is associated with excessive wound repair in a chronic injury model. We hypothesize that in an acute infection, M2 repolarization is important to resolve inflammation and clear debris. However, persistence of these cells in the context of ongoing inflammatory stimuli may contribute to disease pathogenesis.<\/p>\n

In this pilot grant, we seek to uncover the functional consequences of macrophage plasticity and the signaling pathways involved to expand upon a growing interest in macrophage biology in human lung disease. Expanding upon our knowledge will lead to novel therapeutics to modify the immune response in CF lung disease.4 This proposal will address these basic yet unknown areas in macrophage biology as outlined below. Results of these pilot studies will be the basis of larger NIH funded initiatives.<\/p>\n

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P.I.: Ian Sweet, PhD
\nResearch Associate Professor
\nMetabolism, Endocrinology and Nutrition
\nDirector, Islet Core, UW DERC
\nAffiliate Investigator, Benaroya Research Institute<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"

P.I.: Anne Manicone, MD<\/a>
Assistant Professor of Medicine
Center for Lung Biology
Pulmonary and Critical Care Medicine<\/p>

Pulmonary macrophages have dichotomous roles in promoting and resolving inflammatory responses in the lung; and they do this in part by their ability to adopt different activation or polarized states. In an \"M1\" polarized state, they participate in clearance of bacteria and secretion of pro-inflammatory cytokines\/chemokines. They can also adopt an \"M2\" polarized state, and this activation state is important in promoting wound resolution, including clearance of debris and apoptotic neutrophils. A balance of M1 and M2 polarization is likely necessary for a normal inflammatory response to infection; and an imbalance in these activation states may contribute to lung disease. The functional role of M1 and M2 cells in regulating chronic inflammatory diseases is far from clear, and potentially an imbalance of M1\/M2 function may contribute to lung disease. In fact, an increase in M2 cells has been reported in CF airways and is associated with worse lung function.1 Particularly in CF, macrophage polarization may be altered by chronic exposure to apoptotic neutrophils (a stimulus for M2 polarization) and to bacteria (a stimulus for M1 polarization). In addition, other factors specific to or associated with CF, such as a role of CFTR or hyperglycemia in macrophage plasticity and M2 repolarization remain unexplored.<\/p>

My laboratory is interested in the functional roles of M2 cells in acute and chronic lung inflammation and the signaling pathways involved in promoting M2 programming. Our murine studies reveal the following: (1) alveolar macrophage repolarize from M1 to M2 in vivo during the resolution of P. aeruginosa pneumonia, (2) repolarized alveolar macrophages contribute to lung injury resolution in an acute model (not shown), and (3) greater M2 responses is associated with excessive wound repair in a chronic injury model.2,3 We hypothesize that in an acute infection, M2 repolarization is important to resolve inflammation and clear debris. However, persistence of these cells in the context of ongoing inflammatory stimuli may contribute to disease pathogenesis. Our preliminary studies demonstrate that<\/p>

M2 repolarization promotes immunoparalysis to further challenge with endotoxin. Although this may be a favorable response, it may also contribute to chronic bacterial colonization, such as that seen in CF airways. In this pilot grant application, we seek to uncover the functional consequences of macrophage plasticity and the signaling pathways involved to expand upon a growing interest in macrophage biology in human lung disease. Expanding upon our knowledge will lead to novel therapeutics to modify the immune response in CF lung disease.4 This proposal will address these basic yet unknown areas in macrophage biology as outlined below. Results of these pilot studies will be the basis of larger NIH funded initiatives.<\/p>","_et_gb_content_width":"","_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":"","_links_to":"","_links_to_target":""},"categories":[12],"tags":[],"_links":{"self":[{"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/posts\/180"}],"collection":[{"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/comments?post=180"}],"version-history":[{"count":9,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/posts\/180\/revisions"}],"predecessor-version":[{"id":1177,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/posts\/180\/revisions\/1177"}],"wp:attachment":[{"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/media?parent=180"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/categories?post=180"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/depts.washington.edu\/cfrtc\/wp-json\/wp\/v2\/tags?post=180"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}