Laboratory animal models can help to improve our understanding of the mechanistic basis of chronic smoking-related diseases such as emphysema and lung cancer. A/J mice were whole-body exposed to fresh air or to cigarette mainstream smoke from a research reference cigarette in various combinations of inhalation and post-inhalation periods of up to 18 months at daily doses of total particulate matter of up to 3000 mg/m(3) x h. Genes involved in xenobiotic metabolism (e.g., CYP1A1) and oxidative stress (HMOX1) were found to be transiently induced during inhalation periods, returning to control levels directly after cessation of smoke exposure. Genes involved in inflammatory processes (MIP-1alpha) or proteolytic processes (MMP12) displayed sustained induction. Similarly, inflammatory cells and several protein markers in bronchoalveolar lavage showed either a transient induction pattern (PMNLS, TNF-alpha) or a sustained induction pattern (lymphocytes, KC). After 5 months of inhalation, altered lung mechanics (higher tissue elastance and partial loss of elastic recoil) and emphysematous changes (increased mean chord length, decreased bronchial attachments) were observed. In studies of up to 18 months, a dose-dependent increase in the multiplicity of adenomas and adenocarcinomas in the lungs was observed. The causal role of the inflammatory effects in the chronic pathogeneses developing in this mouse model and their relevance to human smoking-related diseases remain to be established.