Early life exposure to nicotine modifies lung gene response after elastase-induced emphysema

Abstract

Background Chronic obstructive pulmonary disease (COPD) is among the top 5 causes of mortality in the world and can develop as a consequence of genetic and/or environmental factors. Current efforts are focused on identifying early life insults and how these contribute to COPD development. In line with this, our study focuses on the influence of early life nicotine exposure and its potential impact on (a) lung pulmonary functions, and (b) elastase-induced emphysema in adulthood. Methods To address this hypothesis, we developed a model of 2 hits, delivered at different time points: mouse pups were first exposed to nicotine/placebo in utero and during lactation, and then subsequently received elastase/placebo at the age of 11 weeks. The effect of nicotine pretreatment and elastase instillation was assessed by (a) measurement of pulmonary function at post-elastase day (ped) 21, and (b) transcriptomic profiling at ped3 and 21, and complementary protein determination. Statistical significance was determined by 3- and 2-way ANOVA for pulmonary functions, and RNAseq results were analyzed using the R project. Results We did not observe any impact of nicotine pre- and early post-natal exposure compared to control samples on lung pulmonary functions in adulthood, as measured by FLEXIVENT technology. After elastase instillation, substantial lung damage was detected by x-ray tomography and was accompanied by loss in body weight at ped3 as well as an increase in cell numbers, inflammatory markers in BAL and lung volume at ped21. Lung functions showed a decrease in elastance and an increase in deep inflation volume and pressure volume (pv) loop area in animals with emphysema at ped21. Nicotine had no effect on elastance and deep inflation volume, but did affect the pv loop area in animals with emphysema at ped21. Extensive transcriptomic changes were induced by elastase at ped3 both in the nicotine-pretreated and the control samples, with several pathways common to both groups, such as for cell cycle, DNA adhesion and DNA damage. Nicotine pretreatment affected the number of lymphocytes present in BAL after elastase instillation and some of the complement pathway related proteins, arguing for a slight modification of the immune response, as well as changes related to general body metabolism. The majority of elastase-induced transcriptomic changes detected at ped3 had disappeared at ped21. In addition, transcriptomic profiling singled out a common gene pool that was independently activated by nicotine and elastase. Conclusions Our study reports a broad spectrum of transient transcriptomic changes in mouse emphysema and identifies nicotine as influencing the emphysema-associated immune system response.

The Role of Licorice Chalcones as Molecular Genes and Signaling Pathways Modulator—A Review of Experimental Implications for Nicotine-Induced Non-Small Cell Lung Cancer Treatment

“…Experimental studies published in English on the effects and/or mechanisms of licorice CHs in nicotine-induced NSCLC treatment were included. Studies were excluded if they focused on emphysema, as it has different cellular and/or molecular mechanisms underlying nicotine-induced lung injury compared to NSCLC [ 36 ]. The search identified 24 experimental studies that met the search criteria, which included 19 in vitro, 1 in vivo, and 4 mixed (in vitro and in vivo).…”

Airspace Diameter Map—A Quantitative Measurement of All Pulmonary Airspaces to Characterize Structural Lung Diseases

“…The C57BL/6J mice used for elastase/saline instillation were randomly allocated (by a coin toss), at 11 weeks of age, to either vehicle or elastase receiving group, with the prerequisite that each group contains comparable numbers of female and male mice. Elastase was administered intranasally, as described previously [29]. Briefly, for pain prevention, 0.1 mg/kg body weight buprenorphine (Temgesic, Indivior Schweiz AG, Baar, Canton of Zug, Switzerland) was admi-nistered subcutaneously 1 h before and 3 h after vehicle/elastase instillation.…”

“…Furthermore, the pipeline can be used to extract and separately analyze any of the lung compartments. To validate our pipeline, we analyzed SRXTM images of two different lung disease models: (i) βENaC-transgenic mice, which develop a cystic fibrosis-like lung disease (CF) [28], and (ii) elastase-induced emphysema [29]. Cystic fibrosis (CF) is an inherited disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator ion channel gene.…”