MAPK Pathway Mediates EGR-1-HSP70-Dependent Cigarette Smoke-Induced Chemokine Production; C.J. Li, W. Ning, M.A. Matthay, C.A. Feghali-Bostwick, A.M. Choi Am J Physiol Lung Cell Mol Physiol. 2007 May; 292(5):L1297.
Cigarette smoking, a major risk factor for chronic obstructive pulmonary disease, can cause airway inflammation, airway narrowing, and loss of elasticity, leading to chronic airflow limitation. In this report, we sought to define the signaling pathways activated by smoke and to identify molecules responsible for cigarette smoke-induced inflammation. We applied cigarette smoke water extract (CSE) to primary human lung fibroblasts and found that CSE significantly increased CXC chemokine IL-8 production. Meanwhile, 70-kDa heat shock protein (HSP70) was also induced by CSE in a dose- and time-dependent manner. CSE treatment stimulated HSP70 secretion by primary fibroblasts, which augmented IL-8 production. This was further confirmed by exogenously added recombinant HSP70. Using HSP70 small interfering RNA, we confirmed that CSE-induced chemokine production was dependent on heat shock protein expression. Further investigation showed that CSE could also stimulate early growth response-1 (EGR-1) in an ERK-dependent manner and that the expression of HSP70 was EGR-1 dependent. In view of these findings, we hypothesize that the MAPK-EGR-1-HSP70 pathway regulates the cigarette smoke-induced inflammatory process.
Comments: While inflammation is recognized as contributing to the pathogenesis of COPD, our understanding of its exact role leading to chronic airway changes and parenchymal destruction remains poorly understood. Further we also recognize that there is a genetic predisposition to developing COPD as only a fraction of smokers develop evidence of chronic airflow limitation. These investigators study the relationship between a transcription factor early growth response 1 (EGR-1) (which has been found to have greater expression in smokers with COPD compared to apparent “healthy” smokers) and well recognized mediators known to be elevated in COPD such as IL-8. This series of elegant bench studies with lung fibroblast NL9 cultured cells demonstrates that cigarette smoke water extract (CES) increases EGR-1 through an ERK1/2 MAPK dependant pathway which in turn increases Heat Shock Protein-70 (HSP70) production leading to an increase in synthesis and release of IL-8. Identification of putative key genetic transcription factors that confer increased risk of developing COPD such as EGR-1 are critical to advance our understanding of the pathogenesis of COPD and possibly for screening to identify those who may be at increased risk of developing COPD. Such insights will have impact on primary and secondary prevention and perhaps also on the development of more specific targeted anti-inflammatory therapies for COPD.
Biomass Fuels Are The Probable Risk Factor of Chronic Obstructive Pulmonary Disease in Rural South China; L. Shengming, Z. Yumin, W. Xiaoping, W. Dali, L. Jiachun, Z. Jingping, Z. Nanshan, R. Pixin. Thorax. 2007 May 4; [Epub ahead of print]
Background: Increasing evidence show the possible association between chronic obstructive pulmonary disease (COPD) and the use of biomass fuels for cooking and heating in developing countries. Data on COPD prevalence and objective measurement of indoor pollution from biomass fuel has not been widely available from China. Objectives: To investigate the prevalence of COPD in two study communities in Guangdong province in China and measure the association between COPD and indoor biomass fuel air pollution. Methods: A cluster-disproportional-random-sampling survey was performed in populations aged over 40 years in urban (Liwang) and rural (Yunyan) areas in Guangdong, China. Spirometry was performed in all subjects and a post-bronchodilator ratio of the forced expiratory volume in the first second over forced vital capacity of less than 0.70 was defined as COPD. Measurements of indoor and outdoor air pollutants were also performed in a random sample of households. Main Results: The overall prevalence of COPD in the two areas (Liwang and Yunyan) was 9.4%. The prevalence of COPD in both whole population and a subpopulation of non-smoking women in rural Yunyan was significantly higher than that in urban Liwang (12.0% vs 7.4%, and 7.2% vs 2.5% respectively). Biomass fuel use was higher in rural Yunyan than that in urban Liwang (88.1% vs 0.7%). Univariate analysis showed significant association between COPD and exposure to biomass for cooking. Multivariate analysis showed the positive association between COPD and urban/rural area (surrogate for exposure to biomass for cooking and local exhaust ventilation in kitchen) after adjustment for gender, age group, BMI, education, occupational exposure, respiratory disease in family, smoking status, life quality and cough in childhood, and similar results were found in non-smoking women. Pollutants measurements showed that CO, PM10, SO2 and NO2 concentrations in the kitchen during biomass fuel combustion were significantly higher than those during LPG combustion. Conclusions: Indoor pollutants from biomass fuels may be an important risk factor for COPD in rural South China.
Comments: In the United States and most “developed” countries, cigarette smoking is the etiological agent for 90 to 95% of all cases of COPD. In the global context however there may be other sources of combustible particulate inhaled in significant quantities capable of inducing chronic airflow limitation and the characteristic features of COPD. This study from China is purported to be the first that prospectively studied the relationship between biomass fuel exposure and the risk of developing COPD. While there are clearly other factors that could contribute to the development of COPD such as occupational dust exposure, cigarette smoking and environmental tobacco smoke exposure, this study showed that there was a higher incidence of COPD in non-smoking women in rural areas and that there was an association between this and higher levels of SO2 exposure (the primary source of which is burning of biomass fuels). The rural homes almost exclusively used biomass fuels for cooking (88.1%)and almost uniformly had no local exhaust ventilation (99.3%) compared to the urban cohort where only 0.7% used biomass fuels and only 11.4% had no local exhaust ventilation in the kitchen. This study is quite unique with its exposure data which supports the contention that in the rural China setting more cases of COPD may be related to use of biomass fuels than cigarette smoke either directly or passively. Clearly in non-smoking women it may represent the main cause for the development of COPD in such settings. Such information should lead to primary prevention efforts and education to reduce biomass fuel exhaust exposure in the areas of the world where they are used as a primary source for cooking and/or heat.
Systemic Effects of Smoking; D.G. Yanbaeva, M.A. Dentener, E.C. Creutzberg, G. Wesseling, E.F. Wouters. Chest. 2007 May; 131(5):1557–66.
Smoking is one of the major lifestyle factors influencing the health of human beings. Life-long cigarette smokers have a higher prevalence of common diseases such as atherosclerosis and COPD with significant systemic impact. The present review evaluates current knowledge concerning possible pathways through which cigarette smoking can affect human health, with special focus on extrapulmonary effects. Long-term smoke exposure can result in systemic oxidants-antioxidants imbalance as reflected by increased products of lipid peroxidation and depleted levels of antioxidants like vitamins A and C in plasma of smokers. A low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies: elevated levels of C-reactive protein (CRP), fibrinogen, and interleukin-6, as well as increased counts of WBC have been reported. Furthermore, rheologic, coagulation and endothelial function markers like hematocrit, blood and/or plasma viscosity, fibrin d-dimer, circulating adhesion molecules (intracellular adhesion molecule-1, selectins), tissue plasminogen activator antigen, and plasminogen activator inhibitor type I are altered in chronic cigarette smokers. Although most of smoking-induced changes are reversible after quitting, some inflammatory mediators like CRP are still significantly raised in ex-smokers up to 10 to 20 years after quitting, suggesting ongoing low-grade inflammatory response persisting in former smokers. New longitudinal epidemiologic and genetic studies are required to evaluate the role of smoking itself and possible gene/environment interplay in initiation and development of smoking-induced common diseases affecting humans.
Comments: This review article from the group at Maastricht University in the Netherlands provides an excellent overview of our current understanding of the systemic effects of cigarette smoking. Physicians are well aware of the associated extra-pulmonary diseases associated with cigarette smoking such as cardiovascular related diseases (coronary artery disease and cerebrovascular disease), extra-pulmonary cancers, and other systemic effects such as osteopenia and cachexia. The precise mechanisms for these effects of cigarette smoke are still poorly understood. These authors provide a concise review of the literature regarding the contributions from oxidative stress and the systemic inflammatory cells and mediators observed to be altered in smokers. As the authors point out we are only at the early stages of understanding the systemic effects of cigarette smoking and the associated extra-pulmonary consequences.