title: Imbalance of mitochondrial-nuclear cross talk in isocyanate mediated pulmonary endothelial cell dysfunction.
abstract: Mechanistic investigations coupled with epidemiology, case-control, cohort and observational studies have increasingly linked isocyanate exposure (both chronic and acute) with pulmonary morbidity and mortality. Though ascribed for impairment in endothelial cell function, molecular mechanisms of these significant adverse pulmonary outcomes remains poorly understood. As preliminary studies conducted in past have failed to demonstrate a cause-effect relationship between isocyanate toxicity and compromised pulmonary endothelial cell function, we hypothesized that direct exposure to isocyanate may disrupt endothelial structural lining, resulting in cellular damage. Based on this premise, we comprehensively evaluated the molecular repercussions of methyl isocyanate (MIC) exposure on human pulmonary arterial endothelial cells (HPAE-26). We examined MIC-induced mitochondrial oxidative stress, pro-inflammatory cytokine response, oxidative DNA damage response and apoptotic index. Our results demonstrate that exposure to MIC, augment mitochondrial reactive oxygen species production, depletion in antioxidant defense enzymes, elevated pro-inflammatory cytokine response and induced endothelial cell apoptosis via affecting the balance of mitochondrial-nuclear cross talk. We herein delineate the first and direct molecular cascade of isocyanate-induced pulmonary endothelial cell dysfunction. The results of our study might portray a connective link between associated respiratory morbidities with isocyanate exposure, and indeed facilitate to discern the exposure-phenotype relationship in observed deficits of pulmonary endothelial cell function. Further, understanding of inter- and intra-cellular signaling pathways involved in isocyanate-induced endothelial damage would not only aid in biomarker identification but also provide potential new avenues to target specific therapeutic interventions.
authors.affiliation: Department of Biotechnology, Dr. H.S. Gour Central University, Sagar, India ; Department of Research, Bhopal Memorial Hospital & Research Centre, Bhopal, India ; School of Studies in Zoology & Biotechnology, Vikram University, Ujjain, India.
authors.forename: Hariom
authors.initials: H
authors.lastname: Panwar
authors.forename: Deepika
authors.initials: D
authors.lastname: Jain
authors.forename: Saba
authors.initials: S
authors.lastname: Khan
authors.forename: Neelam
authors.initials: N
authors.lastname: Pathak
authors.forename: Gorantla V
authors.initials: GV
authors.lastname: Raghuram
authors.forename: Arpit
authors.initials: A
authors.lastname: Bhargava
authors.forename: Smita
authors.initials: S
authors.lastname: Banerjee
authors.forename: Pradyumna K
authors.initials: PK
authors.lastname: Mishra
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017953:Isocyanates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017953:Isocyanates; D017382:Reactive Oxygen Species; C008461:methyl isocyanate
keywords: Endothelial cell apoptosis; Environmental medicine; Mitochondrial oxidative stress; Occupational health; Pulmonary toxicity
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