taurochenodeoxycholic-acid and Asthma

Polymorphism at the 17q21 gene locus and wheezing responses to rhinovirus (RV) early in childhood conspire to increase the risk of developing asthma. However, the mechanisms mediating this gene-environment interaction remain unclear. In this study, we investigated the impact of one of the 17q21-encoded genes,

Topics: A549 Cells; Asthma; Bronchi; Cells, Cultured; Chromosomes, Human, Pair 17; Endoplasmic Reticulum Stress; Epithelial Cells; Fatty Acids, Monounsaturated; Genetic Predisposition to Disease; Genotype; HeLa Cells; Humans; Interferon-beta; Membrane Proteins; Nasal Mucosa; Picornaviridae Infections; Recombinant Proteins; Rhinovirus; RNA Interference; RNA, Small Interfering; Serine C-Palmitoyltransferase; Sphingolipids; Taurochenodeoxycholic Acid; Virus Replication

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Topics: Allergens; Animals; Asthma; Bile Acids and Salts; Chemokines; Cytokines; Female; Humans; Hypersensitivity; Inflammation; Lung; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proteostasis Deficiencies; Pyroglyphidae; Receptors, G-Protein-Coupled; Respiratory Hypersensitivity; Taurochenodeoxycholic Acid; Unfolded Protein Response

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.

Topics: Airway Remodeling; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Drug Evaluation, Preclinical; Endoplasmic Reticulum Stress; Female; Mice, Inbred C57BL; Pyroglyphidae; Respiratory Mucosa; Taurochenodeoxycholic Acid