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Reactive oxygen species ( ROS ) participate in the pathogenesis of emphysema. Among  ROS ‐producing enzymes,  NOX NADPH  oxidases are thought to be responsible for tissue injury associated with several lung pathologies. To determine whether  NOX2  and/or  NOX1  participate in the development of emphysema, their expression patterns were first studied by immunohistochemistry in the lungs of emphysematous patients. Subsequently, we investigated their contribution to elastase‐induced emphysema using  NOX2 ‐ and  NOX1 ‐deficient mice. In human lung,  NOX2  was mainly detected in macrophages of control and emphysematous lungs, while  NOX1  was expressed in alveolar epithelium and bronchial cells. We observed an elevated number of  NOX2 ‐positive cells in human emphysematous lungs, as well as increased   NOX2   and   NOX1    mRNA  expression in mouse lungs following elastase exposure. Elastase‐induced alveolar airspace enlargement and elastin degradation were prevented in  NOX2 ‐deficient mice, but not in  NOX1 ‐deficient mice. This protection was independent of inflammation and correlated with reduced  ROS  production. Concomitantly, an elevation of sirtuin 1 ( SIRT1 ) level and a decrease of matrix metalloproteinase‐9 ( MMP ‐9) expression and activity were observed in alveolar macrophages and neutrophils. We addressed the specific role of macrophage‐restricted functional  NOX2  in elastase‐induced lung emphysema using  Ncf1  mutant mice and  Ncf1  macrophage rescue mice ( Ncf1  mutant mice with transgenic expression of Ncf1 only in  CD68 ‐positive mononuclear phagocytes; the  MN  mouse). Compared to  WT  mice, the lack of functional  NOX2  led to decreased elastase‐induced  ROS  production and protected against emphysema. In contrast,  ROS  production was restored specifically in macrophages from  Ncf1  rescue mice and contributes to emphysema. Taken together, our results demonstrate that  NOX2  is involved in the pathogenesis of human emphysema and macrophage‐specific  NOX2  participates in elastase‐induced emphysema through the involvement of  SIRT1 / MMP ‐9 pathways in mice. © 2014 The Authors.  The Journal of Pathology  published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Macrophage‐specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1 / MMP ‐9 pathways