Synergistic effect of cigarette smoke and bacterial-induced chronic obstructive pulmonary disease type airway inflammation on promotion of K-ras mutant lung cancer

Marco A Ramos, Misha Umer, Susana Castro, Berenice A Gutierrez, Nassim Khosravi, Seyed Javad Moghaddam

Research output: Contribution to conferencePoster


Lung cancer, particularly K-ras mutant lung cancer, is the leading cause of cancer death worldwide, and cigarette smoking (CS) is its main cause. Epidemiologic studies had consistently revealed a strong association (3 to 9 fold increase) between lung cancer and COPD (chronic obstructive pulmonary disease), after controlling for CS exposure. COPD is an inflammatory disease of the airways with smoking being the main cause of it. Importantly, lung inflammation persists and lung function continues to deteriorate as does the increased risk of lung cancer even after cessation of cigarette smoking among former smokers with COPD. These facts suggest a strong link between COPD-related airway inflammation and lung cancer promotion independent of smoking. We have previously shown that weekly exposure to an aerosolized bacterial lysate of nontypeable Haemophilus influenzae (NTHi), induces lung inflammation with a profile of mediators and inflammatory cells similar to that observed in COPD patients excluding mucous metaplasia. We further showed that NTHi-induced COPD type airway inflammation promotes lung cancer 3.2-fold in a K-ras mutant mouse model remarkably similar to that in the epidemiologic literature. NTHi is the most common colonizing bacteria in the lower respiratory tract of patients with COPD and could be a potential cause of perpetuating and promoting persistent airway inflammation after CS exposure in these patients. Therefore, we further studied the effect of combined CS and NTHi exposure in the induction of COPD phenotype and promotion of lung cancer. Briefly, 6-week old K-ras mutant mice were exposed to NTHi lysate once a week for 8 weeks and to cigarette smoke (CS) daily for 2 hours/day, 5 days/week for 8 weeks and studied at the age of 14 weeks. The CS exposure was conducted by burning 3R4F reference cigarettes (University of Kentucky, Tobacco Research Institute), using an InExpose System (SCIREQ Scientific Respiratory Equipment Inc). We found that CS exposure alone caused a mild macrophage dominant airway inflammation, induced airway epithelial mucous metaplasia, and led to a 2.3 fold increase in lung tumor burden. Notably, combined NTHi and CS exposure resulted in a robust neutrophilic lung inflammation and mucous metaplasia and promoted K-ras mutant lung cancer by 4.3 folds (2 times more than CS alone). Our experimental results suggest that CS exposure and colonization of smoke-injured airways with NTHi induce an inflammatory and structural COPD phenotype fully recapitulating human COPD and provide a microenvironment that has a significant promoting effect on K-ras mutant lung cancer.
Original languageEnglish (US)
StatePublished - 2018
Externally publishedYes


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