The Kinetics of Transcriptomic Changes Induced by Cigarette Smoke in Rat Lungs Reveals a Specific Program of Defense, Inflammation, and Circadian Clock Gene Expression

Abstract

Gene expression profiling in animal models exposed to cigarette mainstream smoke (CS) shapes up as a promising tool for investigating the molecular mechanisms involved in the onset and development of CS-related disease and may aid in the identification of disease candidate genes. Here we report on differential gene expression in lungs of rats exposed for 2, 7, and 13 weeks to 300 and 600 microg total particulate matter/l CS with sacrifice 2, 6, or 20 h after the last exposure. Regarding antioxidant and xenobiotic-metabolizing (phase I/II) enzymes, a stereotypic, mostly transient, expression pattern of differentially expressed genes was observed after each exposure period. The expression patterns were generally dose dependent for antioxidant and phase II genes and not dose dependent for phase I genes at the CS concentrations tested. However, with increasing length of exposure, there was a distinct, mostly sustained and dose-sensitive, expression of genes implicated in innate and adaptive immune responses, clearly pointing to an emerging inflammatory response. Notably, this inflammatory response included the expression of lung disease-related genes not yet linked to CS exposure, such as galectin-3, arginase 1, and chitinase, as well as genes encoding proteolytic enzymes. Finally, our experiments also revealed a CS exposure-dependent shift in the cyclical expression of genes involved in controlling the circadian rhythm. Altogether, these results provide further insight into the molecular mechanisms of CS-dependent disease onset and development and thus may also be useful for defining CS-specific molecular biomarkers of disease.

Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages

“…Infection by Nb induces a strong Th2 immune response and is known to activate alternative macrophages [19]; however, their long-term presence in the airways suggests that additional mechanisms flowing on from the original infection may sustain their renewal and differentiation. Notably, microarray analysis of lungs from smokeinduced emphysema [22] show a similar pattern of gene expression to that described here; specifically, the upregulation of alternatively activated macrophage markers including FIZZ, YM1, and AMcase and the protease MMP-12. It has been proposed that alternatively activated macrophages may play a role in tissue repair and dampening down responses, and thus their presence in these models of emphysema might be explained by the host-tissue repair response.…”

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

“…The ineffectiveness of SRT1720 on LPS-mediated proinflammatory cytokine release in PBMCs recovered from patients with COPD may be attributed to dramatic SIRT1 reduction and molecular clock dysfunction (e.g., acetylation and degradation of BMAL1 and PER2). In addition to the suprachiasmatic nucleus, peripheral tissues including lung, liver, heart, and kidney also possess selfsustaining, gene-based circadian clocks oscillating with a period of approximately 24 hours, which play a critical role in optimizing the organization of cellular function and responses to environmental stimuli (6,(27)(28)(29). Abnormal regulation of circadian clocks in peripheral tissues is suggested to cause cell dysfunction and chronic diseases (8,30).…”

Molecular pathogenesis of emphysema

“…A few elements of this concept are discussed here. Lung gene expression profiling of cigarette smoke-exposed rats demonstrated a sustained, increased expression of a number of genes implicated in the innate and adaptive immune responses (74). Chronic lung cell damage, and in particular apoptosis, when combined with ineffective phagocytic removal of apoptosed cell bodies (37) may result in the generation of neoantigens (for example, nucleosomes or DNA fragments; ref.…”