Chronic exposure to cigarette smoke is the leading cause of lung cancer and chronic obstructive pulmonary disease. The A/J mouse model is used to evaluate lung inflammation, lung cancer development, toxicological impact and the underlying molecular changes upon life-time exposure to cigarette smoke (CS) from a reference cigarette 3R4F or to aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product (cMRTP). A/J mice were exposed for 6 hours per day for 5 days per week with planned total exposure duration of 18 months. Quantification of pulmonary inflammation, lung function tests, histopathological evaluation, toxicological assessment as well as transcriptome and proteome analysis of respiratory tract organs were performed at interim dissections. Exposure to CS induced changes in red blood cell profiles that are consistent with high carbon monoxide in CS smoke but were not observed following THS2.2 aerosol exposure. Exposure to CS also resulted in pulmonary inflammation, altered lung function and molecular changes that are suggestive of emphysema but only minimal effects were observed following THS2.2 aerosol exposure. Significant changes in the airway transcriptome and proteome were observed following CS exposure, but only few genes and proteins were altered following THS2.2 aerosol exposure. Biological network analysis identified perturbed molecular processes that are consistent with CS exposure, but only minor perturbations of cell stress responses were noted following THS2.2 aerosol exposure. In summary, lung inflammation and the associated loss of pulmonary function and molecular perturbations were significantly reduced in mice exposed to aerosol from THS2.2 as compared to CS exposure.