<p>Cigarette smoke exposure reduces leukemia inhibitory factor levels during respiratory syncytial viral infection</p>

Abstract

Background: Viral infections are considered a major driving factor of chronic obstructive pulmonary disease (COPD) exacerbations and thus contribute to disease morbidity and mortality. Respiratory syncytial virus (RSV) is a frequently detected pathogen in the respiratory tract of COPD patients during an exacerbation. We previously demonstrated in a murine model that leukemia inhibitory factor (LIF) expression was increased in the lungs during RSV infection. Subduing LIF signaling in this model enhanced lung injury and airway hypersensitivity. In this study, we investigated lung LIF levels in COPD patient samples to determine the impact of disease status and cigarette smoke exposure on LIF expression. Materials and methods: Bronchoalveolar lavage fluid (BALF) was obtained from healthy never smokers, smokers, and COPD patients, by written informed consent. Human bronchial epithelial (HBE) cells were isolated from healthy never smokers and COPD patients, grown at the air–liquid interface and infected with RSV or stimulated with polyinosinic:polycytidylic acid (poly (i:c)). Mice were exposed to cigarette smoke daily for 6 months and were subsequently infected with RSV. LIF expression was profiled in all samples. Results: In human BALF, LIF protein was significantly reduced in both smokers and COPD patients compared to healthy never smokers. HBE cells isolated from COPD patients produced less LIF compared to never smokers during RSV infection or poly (i:c) stimulation. Animals exposed to cigarette smoke had reduced lung levels of LIF and its corresponding receptor, LIFR. Smoke-exposed animals had reduced LIF expression during RSV infection. Two possible factors for reduced LIF levels were increased LIF mRNA instability in COPD epithelia and proteolytic degradation of LIF protein by serine proteases. Conclusions: Cigarette smoke is an important modulator for LIF expression in the lungs. Loss of LIF expression in COPD could contribute to a higher degree of lung injury during virus-associated exacerbations.

Viral respiratory infections and air pollutants

“…Among the mechanisms involved are cigarette smoke's ability to induce necrosis during RSV infection facilitates viral replication in the respiratory tract (Groskreutz et al 2009). Additionally, RSV can negatively modulate the antiviral response mediated by interferon, as well as diminish the production of cytokines and chemokines, such as IL-1β, CXCL10 (Castro et al 2011), and leukemia inhibitory factor (LIF), which has an important role in the prevention of lung injury (Poon et al 2019), thus increasing the susceptibility to infection, particularly in those individuals exposed to cigarette smoke in a chronic way (Modestou et al 2010) (Fig. 2).…”

<p>Mechanisms by Which the MBD2/miR-301a-5p/CXCL12/CXCR4 Pathway Regulates Acute Exacerbations of Chronic Obstructive Pulmonary Disease</p>

“…Human pulmonary microvascular endothelial cells (HULEC-5a) 25 and human lung bronchial epithelial (HBE) cells 26 , 27 were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA). The HULEC-5a cells were cultured in MCDB131 medium containing 10% heat-inactivated fetal bovine serum (FBS), EGF (10 μg/mL), and hydrocortisone (1 μg/mL) at 37°C in a 5% CO 2 atmosphere.…”

Molecular Mechanisms of RSV and Air Pollution Interaction: A Scoping Review

“…LIF might be regulated by various factors, including an inhibition by IFN-γ or an enhancement by IL-1β [ 111 , 112 ]. A study on human subjects (BALF from volunteers: never smokers, smokers, and COPD patients) revealed lower LIF protein concentrations in BALF from smokers and COPD patients [ 51 ]. Human bronchial epithelial cells obtained from COPD patients BALF showed much lower LIF production upon RSV infection compared to healthy volunteers’ epithelial cells [ 51 ].…”

“…A study on human subjects (BALF from volunteers: never smokers, smokers, and COPD patients) revealed lower LIF protein concentrations in BALF from smokers and COPD patients [ 51 ]. Human bronchial epithelial cells obtained from COPD patients BALF showed much lower LIF production upon RSV infection compared to healthy volunteers’ epithelial cells [ 51 ]. An animal model also disclosed a lower LIF and its receptor, LIFR, levels during an RSV infection in mice exposed to cigarette smoke [ 51 ].…”

“…Human bronchial epithelial cells obtained from COPD patients BALF showed much lower LIF production upon RSV infection compared to healthy volunteers’ epithelial cells [ 51 ]. An animal model also disclosed a lower LIF and its receptor, LIFR, levels during an RSV infection in mice exposed to cigarette smoke [ 51 ].…”