Retinoic acid signaling is essential for airway smooth muscle homeostasis

Abstract

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway

“…COL6A3 was upregulated after radiation when RA was reduced. COL6A3 was previously reported as upregulated in RA-deficient airway smooth muscle cells in both mouse and human (Chen et al 2018). One of the targets that YAP1 regulates is DHRS3, a key enzyme in RA biosynthesis (Billings et al 2013).…”

Kinase inhibitors in the treatment of obstructive pulmonary diseases

“…For example, ERK activation of AP-1 promotes increased ASM cell proliferation, while activation of the retinoic acid receptor (RAR) is a negative regulator of AP-1 and ASM cell proliferation [65,66]. Loss of retinoic acid (RA) signaling has been linked to hypertrophy and hypercontractility of ASM cells, suggesting defects in RA may contribute to obstructive pulmonary disease [67]. Thus, combining ERK inhibitors and RAR agonists could effectively control ASM cell proliferation and airway remodeling in asthma.…”

Oncogenic Gene-Expression Programs in Leiomyosarcoma and Characterization of Conventional, Inflammatory, and Uterogenic Subtypes

“…Notable is the high expression in LMS of CRABP1 and CRABP2, which are responsible for all-trans-retinoic acid binding and shuttling to metabolic enzymes and nuclear receptors (44). Given the role of retinoic acid signaling in smooth-muscle cell homeostasis, proliferation, and differentiation (45), these data suggest this pathway may be activated and important in LMS. Taken together, these results highlight a small group of recurrently amplified and highly expressed genes in LMS, and further testing is needed to explore their utility as diagnostic markers or therapeutic vulnerabilities.…”