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Role of Calcium‐Sensor in bromine‐induced lung hyper‐reactivity
Author(s) -
Lazrak Ahmed,
Creighton Judy,
Laube Mandy,
Yu Zhihong,
Matalon Sadis
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.551.6
Subject(s) - nifedipine , chemistry , diltiazem , calcium , bromine , depolarization , endocrinology , calcium in biology , calcium channel , pharmacology , medicine , voltage dependent calcium channel , l type calcium channel , organic chemistry
Exposure to bromine causes major injuries to skin and internal organs. In the lung, the exposure to bromine causes symptoms similar to asthma. When mice were exposed to 600 ppm bromine for 30 minutes, they developed lung hyper‐reactivity. 50% of the exposed animals died when treated with 5 mg/kg of L‐type calcium channel inhibitor nifedipine compared to controls. In contrast, treatement with 5mg/kg of diltiazem, a non dihydropyridine L‐type calcium channel blocker, protected animals from the injury induced by bromine. Exposure of human or murine Airway Smooth Muscle Cells (ASMC) to 100 ppm bromine for 10 minutes caused membrane potential (V m ) depolarization from −62±3 mV to −45±5 mV, p <0.001. Nifedipine exacerbated V m depolarization to −15±10 mV, p<0.001; however diltiazem helped V m recovery to −55±5 mV, p< 0.001. Using Fura‐2 AM, we found bromine injury to increase intracellular calcium (Ca i ) in human and murine ASMC. Ca i was reduced by diltiazem but not nifedipine. the nifedipine caused Ca i increase was dose dependent with an EC 50 of 200 nM. Western blot studies showed an increase of Calcium Sensor (CaSR) expression in human and murine ASMC exposed to bromine and to Low Molecular Weight Hyaluronic Acid (LMW‐HA). LMW‐HA is formed by the breakdown of high molecular weight hyaluronic acid by bromine. The knockdown of the CaSR with siRNA significantly reduced nifedipine induced V m depolarization, and Ca i increase in both human and murine ASMC exposed to bromine or LMW‐HA. In conclusion, lung hyper‐reactivity induced by bromine is caused by an increase in CaSR expression in ASMC mediated by LMW‐HA. Support or Funding Information Grants: 1U01ES027697‐01, 5U01ES026458‐02, and SAB100322373 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .