Epigenetic underpinnings of inflammation: Connecting the dots between pulmonary diseases, lung cancer and COVID-19

Abstract

Inflammation is an essential component of several respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and acute respiratory distress syndrome (ARDS). It is central to lung cancer, the leading cancer in terms of associated mortality that has affected millions of individuals worldwide. Inflammation and pulmonary manifestations are also the major causes of COVID-19 related deaths. Acute hyperinflammation plays an important role in the COVID-19 disease progression and severity, and development of protective immunity against the virus is greatly sought. Further, the severity of COVID-19 is greatly enhanced in lung cancer patients, probably due to the genes such as ACE2, TMPRSS2, PAI-1 and furin that are commonly involved in cancer progression as well as SAR-CoV-2 infection. The importance of inflammation in pulmonary manifestations, cancer and COVID-19 calls for a closer look at the underlying processes, particularly the associated increase in IL-6 and other cytokines, the dysregulation of immune cells and the coagulation pathway. Towards this end, several reports have identified epigenetic regulation of inflammation at different levels. Expression of several key inflammation-related cytokines, chemokines and other genes is affected by methylation and acetylation while non-coding RNAs, including microRNAs as well as long non-coding RNAs, also affect the overall inflammatory responses. Select miRNAs can regulate inflammation in COVID-19 infection, lung cancer as well as other inflammatory lung diseases, and can serve as epigenetic links that can be therapeutically targeted. Furthermore, epigenetic changes also mediate the environmental factors-induced inflammation. Therefore, a better understanding of epigenetic regulation of inflammation can potentially help develop novel strategies to prevent, diagnose and treat chronic pulmonary diseases, lung cancer and COVID-19.

Keywords: ARDS; COPD; COVID-19; Epigenetics; Inflammation; Lung cancer.

Fig. 1

Inflammation connects COVID-19 and cancer with pulmonary diseases. In addition to genetic predisposition, several extrinsic factors such as, bacterial / viral infections and environmental agents can cause inflammation, with an emerging realization for the involvement of epigenetic regulation. Inflammation leads to pulmonary manifestations exemplified by ARDS and COPD, which are observed in COVID-19 as well as lung cancer patients.

Fig. 2

Key molecular factors connecting lung cancer and COVID-19. A number of key cell surface proteins and enzymes play parallel roles in lung cancer progression and SARS-CoV-2 infection. A majority of them seem to play a role in the entry of SARS-CoV-2 into host cells while also being reported to be elevated in metastatic lung cancers.

Fig. 3

Epigenetic regulation of inflammation. A number of epigenetic events can regulate inflammation. Modulators such as methylation and acetylation maintain a balance between heterochromatin and euchromatin with the relaxed euchromatin favoring transcription of genes. Histone acetyltransferases (HATs) and other proteins with similar activity such as bromodomain-containing protein 4 (BRD4) acetylate histones while histone deacetylases (HDACs) remove acetyl groups from histones. Methylation of DNA and histones is carried out by methyltransferases while demethylases are responsible for demethylating action. Finally, regulation through non-coding RNAs (both long non-coding RNAs ‘lncRNAs’ and microRNAs ‘miRNAs’) also comprises epigenetic regulation of inflammation. The overall result of such epigenetic events is either induction or resolution of inflammation with induction of inflammation manifested by release of pro-inflammatory cytokines, chemokines and chemokine receptors along with mobilization of neutrophils/ macrophages, elevated neutrophils-to-lymphocytes ratio (NLR) and coagulation. All these manifestations finally result in lung injury and pulmonary diseases characterized by chronic obstructive pulmonary disease (COPD) and/or acute respiratory distress syndrome (ARDS).