RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

Abstract

Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho-kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper-responsiveness, b-adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho-kinase, cytokine and epigenetic regulation of RhoA/Rho-kinase, and the role of RhoA/Rho-kinase in regulating major features of asthma, such as airway hyperresponsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho-kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho-kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho-kinase signalling may be a promising therapeutic target for the treatment of asthma.

Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early-life allergen exposure

“…Another possible contributor is RhoA, a TGF-β–inducible molecule that was highly expressed in pediatric AMs in our study and has been implicated in macrophage polarization and function. 45 …”

Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor–RhoA Axis in Asthma

“…To further address the relative contribution of AhR in the activation of the TGFβ1/Smad3 signaling axis, we studied its underlying mechanisms by focusing on RhoA/Rho-kinase signaling. RhoA is a nucleotide-dependent protein, switching between an inactive form, GDP-bound RhoA, and an active form, GTP-bound RhoA, and has been shown to regulate various biological functions, including cell differentiation, differentiation, recruitment, and apoptosis (37,57,58). Increased expression and activation of RhoA have been associated with asthma (59)(60)(61)(62).…”

“…mechanisms regarding the regulation of TGFβ1 signaling, which may provide novel insights into the mechanisms that lead to allergic airway inflammation. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma (37). Studies including ours have suggested a positive loop between RhoA/Rho-kinase signaling and TGFβ1 that drives airway constriction, airway hyper-responsiveness, and airway remodeling in asthma (38)(39)(40)(41), raising the possibility that RhoA/Rho-kinase signaling may be one of the central pathways in regulating allergen-induced TGFβ1 activation.…”

Scutellaria baicalensis and Their Natural Flavone Compounds as Potential Medicinal Drugs for the Treatment of Nicotine-Induced Non-Small-Cell Lung Cancer and Asthma

“…TNF-α, IL-13, IL-4, IL-17A and CCL2 are found to increase RhoA mRNA expression via NF-κβ and STAT6 signaling pathways activation, leading to airway hyperreactivity in asthma. Activation of TGF-β1 also has a key role in hASM contraction by increasing RhoA/ROCK-medicated phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin light chain (MLC) through PI3K signaling pathway activation [ 97 ].…”