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Agonistic induction of PPAR? reverses cigarette smoke-induced emphysema.

ABSTRACT: The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator-activated receptor ? (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPAR? in APCs using Cd11c-Cre Pparg(flox/flox) mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg(flox/flox) mice required OPN, suggesting an antiinflammatory mechanism in which PPAR? negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPAR? agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPAR? agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPAR? activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

SUBMITTER: Shan M

PROVIDER: S-EPMC3934169 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema.

Shan Ming M You Ran R Yuan Xiaoyi X Frazier Michael V MV Porter Paul P Seryshev Alexander A Hong Jeong-Soo JS Song Li-zhen LZ Zhang Yiqun Y Hilsenbeck Susan S Whitehead Lawrence L Zarinkamar Nazanin N Perusich Sarah S Corry David B DB Kheradmand Farrah F

The Journal of clinical investigation 20140224 3

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in respo ...[more]

PMID: 24569375

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Project description:RationaleMatrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction.ObjectivesTo determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples.MethodsMouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury.Measurements and main resultsMice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage.ConclusionsThese results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

Dataset Information

Agonistic induction of PPAR? reverses cigarette smoke-induced emphysema.

Publications

Agonistic induction of PPARγ reverses cigarette smoke-induced emphysema.

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