Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract

Sang-Eun Kim,Jai Youl Ro,Yun-Song Lee,Tran Thi Thanh Thuy,Yeon-Mock Oh,Ji-Hyun Lee,Young-An Bae,Dong-Soon Lee,Jee-Yin Ahn,Yoon Kong,Sang-Do Lee

doi:10.3858/emm.2009.41.4.031

Abstract

Matrix metalloproteinase-9 (MMP-9) may play an important role in emphysematous change in chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality and morbidity worldwide. We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, attenuates emphysematous change and MMP-9 induction in the lungs of rats exposed to cigarette smoke. However, it remained uncertain how cigarette smoke induced MMP-9 and how simvastatin inhibited cigarette smoke-induced MMP-9 expression in alveolar macrophages (AMs), a major source of MMP-9 in the lungs of COPD patients. Presently, we examined the related signaling for MMP-9 induction and the inhibitory mechanism of simvastatin on MMP-9 induction in AMs exposed to cigarette smoke extract (CSE). In isolated rat AMs, CSE induced MMP-9 expression and phosphorylation of ERK and Akt. A chemical inhibitor of MEK1/2 or PI3K reduced phosphorylation of ERK or Akt, respectively, and also inhibited CSE-mediated MMP-9 induction. Simvastatin reduced CSE-mediated MMP-9 induction, and simvastatin-mediated inhibition was reversed by farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). Similar to simvastatin, inhibition of FPP transferase or GGPP transferase suppressed CSE-mediated MMP-9 induction. Simvastatin attenuated CSE-mediated activation of RAS and phosphorylation of ERK, Akt, p65, IkappaB, and nuclear AP-1 or NF-kappaB activity. Taken together, these results suggest that simvastatin may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of RAS in the signaling pathways, in which Raf-MEK-ERK, PI3K/Akt, AP-1, and IkappaB-NF-kappaB are involved.

Highlights

Chronic obstructive pulmonary disease (COPD) is characterized by progressive and irreversible airflow limitation, which is usually associated with an abnormal inflammatory response to noxious particles or gases, mainly cigarette smoke (Rabe et al, 2007)
(Lee et al, 2005), we demonstrated that simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, can successfully attenuate emphysematous changes and reduce the increase in matrix metalloproteinase (MMP)-9 activities in the lung tissues of rats exposed to cigarette smoke for 16 weeks
We have demonstrated that cigarette smoke extract (CSE) induces Matrix metalloproteinase-9 (MMP-9) with activation of RAS, ERK, and exposure, and GGPP transferase inhibitor (GGTI)-2133 or farnesyl transferase inhibitor (FTI)-277 was added 4 h before CSE

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by progressive and irreversible airflow limitation, which is usually associated with an abnormal inflammatory response to noxious particles or gases, mainly cigarette smoke (Rabe et al, 2007). Emphysema is caused by destruction of walls of the distal airways and alveolar sacs, leading to enlargement of airspaces. Cigarette smoke harbors a multitude of chemical compounds and causes direct oxidative lung damage and indirect damage through the activation of various lung cells including alveolar macro-. The number of AMs is elevated in sputum, bronchoalveolar lavage fluid, airways, and lung parenchyma of smokers and patients with COPD (Barnes, 2004). AMs are localized to the sites of alveolar wall destruction in patients with emphysema (Finkelstein et al, 1995; Meshi et al, 2002). AMs activated by cigarette smoke extract (CSE) release inflammatory mediators such as TNF-α (Churg et al, 2003) and IL-8 (Culpitt et al, 2003) to provoke inflammation in the lungs of the individual smoker

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Conclusion