STAT3 modulates cigarette smoke-induced inflammation and protease expression

Patrick Geraghty,Robert Foronjy,Anne E Wyman,Abdoulaye J Dabo,Itsaso Garcia-Arcos,Sonya Gadhvi

doi:10.3389/fphys.2013.00267

Abstract

Signal transducer and activator of transcription-3 (STAT3) regulates inflammation, apoptosis, and protease expression, which are critical processes associated with airway injury and lung tissue destruction. However, the precise role of STAT3 in the development of airway diseases such as chronic obstructive pulmonary disease (COPD) has not been established. This study shows that cigarette smoke activates STAT3 in the lungs of mice. Since cigarette smoke activated STAT3 in the lung, we then evaluated how the loss of STAT3 would impact on smoke-mediated lung inflammation, protease expression, and apoptosis. STAT3+/+ and STAT3−/− mice were exposed to 8 days of cigarette smoke. Compared to the STAT3+/+ mice bronchoalveolar lavage fluid (BALF) cellularity was significantly elevated in the STAT3−/− mice both before and after cigarette smoke exposure, with the increase in cells primarily macrophages. In addition, smoke exposure induced significantly higher BALF protein levels of Interleukin-1α (IL-1α), and monocyte chemotactic protein-1 (MCP-1) and higher tissue expression of keratinocyte chemoattractant (KC) in the STAT3−/− mice. Lung mRNA expression of MMP-12 was increased in STAT3−/− at baseline. However, the smoke-induced increase in MMP-10 expression seen in the STAT3+/+ mice was not observed in the STAT3−/− mice. Moreover, lung protein levels of the anti-inflammatory proteins SOCS3 and IL-10 were markedly lower in the STAT3−/− mice compared to the STAT3+/+ mice. Lastly, apoptosis, as determined by caspase 3/7 activity assay, was increased in the STAT3−/− at baseline to levels comparable to those observed in the smoke-exposed STAT3+/+ mice. Together, these results indicate that the smoke-mediated induction of lung STAT3 activity may play a critical role in maintaining normal lung homeostasis and function.

Highlights

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States (Murphy et al, 2012) and it is projected to become the third leading cause worldwide within the 20 years (Raherison and Girodet, 2009)
Since Signal transducer and activator of transcription-3 (STAT3) expression is increased in COPD, our study examined how cigarette smoke exposure impacted on STAT3 activation in the lungs of mice over the course of 1 year
CIGARETTE SMOKE INDUCES STAT3 ACTIVATION IN MOUSE LUNGS To determine the STAT3 response to cigarette smoke, STAT3 activity was measured in the nuclear fraction of the lungs of C57Bl/6 mice subjected to varying periods of smoke exposure

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States (Murphy et al, 2012) and it is projected to become the third leading cause worldwide within the 20 years (Raherison and Girodet, 2009). In contrast to other diseases, the age-adjusted mortality for COPD has increased over the past 30 years (Miller et al, 2000). Current pharmacological therapies improve lung function and slow disease progression but they have not been shown to impact on COPD mortality (Kim and Criner, 2013). Cigarette smoke is the major etiologic factor associated with this disorder and prolonged exposure to cigarette smoke induces damaging inflammatory, apoptotic, and proteolytic responses in the lung (Macnee, 2007). These biological processes lead to dysfunctional matrix remodeling that cause airway obstruction and lung tissue destruction (Cornwell et al, 2010).

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