title: Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice.
abstract: Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.
authors.affiliation: 1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Vaz
authors.affiliation: 2 Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Subbiah
authors.initials: S
authors.lastname: Rajasekaran
authors.affiliation: 2 Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Haranatha R
authors.initials: HR
authors.lastname: Potteti
authors.affiliation: 2 Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Sekhar P
authors.initials: SP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002908:Chronic Disease; D006801:Humans; D007249:Inflammation; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D011656:Pulmonary Emphysema; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099169:Fos-Related Antigen 1
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1
keywords: activator protein-1; emphysema; inflammation; lung; macrophages