MicroRNA‐mediated inflammation and coagulation effects in rats exposed to an inhaled analog of sulfur mustard

Abstract

Exposure of rats to 2-chloroethyl ethyl sulfide (CEES), an analog of sulfur mustard, can cause acute lung injury (ALI), resulting in increased inflammation and coagulation and altered levels of plasma microRNAs (miRNAs). Rats were exposed to aerosolized CEES and euthanized 12 h later for collection of tissue and plasma. Profiling of miRNAs in plasma, using a TaqMan-based RT-PCR array, revealed 14 differentially expressed miRNAs. Target gene prediction and pathway analysis revealed miRNA-mediated regulation of organismal injury, inflammation, and respiratory diseases. miR-140-5p, a marker of ALI, was downregulated in the plasma, lung, liver, and kidney of CEES-exposed rats, with a concomitant increase in the expression of the inflammation markers IL-6 and IL-1α and the coagulation marker tissue factor (F3). Exposure of rat airway epithelial cells (RL-65) to CEES (0.5 mM) caused cell death and a decrease in miR-140-5p both in cells and media supernatant. This was accompanied by an increase in cellular mRNA levels of IL-6, IL-1α, and F3, as well as FGF9 and EGR2, putative targets of miR-140. Knockdown of miR-140 by specific oligos in RL-65 cells mimicked the in vivo CEES-mediated effects, leading to significantly increased mRNA levels of IL-6, IL-1α, F3, FGF9, and EGR2. Our study identifies miR-140-5p as a mediator of CEES-induced ALI, which could potentially be targeted for therapy.

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

“…Proinflammatory cytokines are produced predominantly by activated immune cells which trigger inflammatory reactions. Based on the earlier reports and our own findings [ 89 , 221 ], IL-6 is clearly an important pro-inflammatory cytokine in pulmonary and non-pulmonary diseases, which can be regulated epigenetically. IL-6 in turn, can epigenetically regulate other molecular factors.…”

“…Even the tumor associated neutrophils (TANs) aid lung cancer tumorigenesis through increased expression of chemokine receptors such as CXCR3/4, CCR5/7 along with secretion of pro-inflammatory factors such as IL-6, IL-8 and MCP-1 [ 86 ]. IL-6 is produced at inflammation sites [ [87] , [88] , [89] ] and it promotes lung cancer metastasis [ 90 ]. High circulating levels of IL-6 associate with poor prognosis of lung cancer patients [ 91 ] thus making case for IL-6 blockage as an effective anticancer therapy [ 92 ].…”

miR-346 regulates the development of ARDS by regulating the function of pulmonary microvascular endothelial cells

“…In recent years, studies on ARDS patients have found that miRNA expression is abnormal. CEES [ 23 ] exposure can also lead to differential expression of miRNAs in rat plasma [ 24 ]. It has been found that miR-346 expression is upregulated in rats, targeting multiple mRNAs [ 16 ].…”

Deciphering the role of microRNAs in mustard gas–induced toxicity

“…The role of miRNAs in the toxicity induced by 2chloroethyl ethyl sulfide (CEES), an inhaled monofunctional analog of SM, was elucidated recently by Rana et al in a cellular model and male Sprague-Dawley rats. 123 The effects observed in this study were acute effects, studied 12 h after CEES exposure in rats and 24 h after CEES exposure in the cell culture. The authors observed significant downregulation of miR-140-5p, which is a marker of ALI, in multiple organs of CEES-exposed rats and in rat airway epithelial cells as compared with the respective controls.…”

“…125 Rana et al further proposed on the basis of their study that miR-140-5p could prove to be a useful target to mitigate the toxic effects of SM exposure. 123 Benefits of deciphering the role of miRNAs in SM-induced toxicity miRNAs have emerged as integral components in the regulation of the genetic machinery; however, their precise role in myriad of pathways is still relatively novel and unexplored in the field of biological sciences. Nonetheless, numerous studies on the role of miRNAs in SM-induced toxicity have been conducted that provide two benefits.…”