title: Chemical chaperones mitigate experimental asthma by attenuating endoplasmic reticulum stress.
abstract: Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.
authors.affiliation: 1 Centre of Excellence for Translational Research in Asthma & Lung Disease; and.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Makhija
authors.forename: Veda
authors.initials: V
authors.lastname: Krishnan
authors.forename: Rakhshinda
authors.initials: R
authors.lastname: Rehman
authors.forename: Samarpana
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Shuvadeep
authors.initials: S
authors.lastname: Maity
authors.forename: Ulaganathan
authors.initials: U
authors.lastname: Mabalirajan
authors.forename: Kausik
authors.initials: K
authors.lastname: Chakraborty
authors.forename: Balaram
authors.initials: B
authors.lastname: Ghosh
authors.forename: Anurag
authors.initials: A
authors.lastname: Agrawal
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005990:Glycerol / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000187:drug effects; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology; D017510:Protein Folding / Q000187:drug effects; D014199:Trehalose / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D008744:Methylamines; D018832:Molecular Chaperones; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D014199:Trehalose; C005855:trimethyloxamine; D005990:Glycerol