Bronchial Smooth Muscle Contraction Research Articles

Salbutamol in the Management of Asthma: A Review.

Asthma is a common inflammatory disease of the lungs. The prevalence of asthma is increasing worldwide, and the tendency indicates that the number of asthma sufferers will soar in the coming years for several reasons, in particular, the lifestyles we have adopted that expose us to risk factors. Salbutamol is the first selective short-acting β2-agonist (SABA) used as an alternative reliever in the treatment of asthma. Its therapeutic effect is based on its potent smooth muscle relaxant properties, which allow the inhibition of bronchial smooth muscle contraction and subsequent bronchodilation. Salbutamol can be administered orally, intravenously (IV), intramuscularly (IM), subcutaneously, or by inhalation. For this reason, the pharmacokinetic (PK) parameters-absorption, distribution, metabolism, and elimination-are highly diverse and, consequently, the efficacy and adverse effects also differ between each formulation. Here, we review the pharmacological profile of different salbutamol formulations, focusing on their efficacy and adverse effects for its original application, asthma.

Recent Findings on the Mechanism of Cough Hypersensitivity as a Cause of Chronic Cough

An increasing number of patients complain to medical institutions about a cough that persists for more than 8 weeks, namely chronic cough. The cough observed in patients with chronic cough is not responsive to conventional antitussive agents such as dihydrocodeine and dextromethorphan, and this is a major clinical problem. The most common pathology of chronic cough in Japan is dry cough. Two causes of dry cough are increased sensitivity of cough receptors (cough hypersensitivity) and increased contraction of bronchial smooth muscle. Among these, the mechanisms of cough hypersensitivity are diverse, and understanding these mechanisms is important for the diagnosis and treatment of chronic cough. In this paper I will review the regulatory mechanisms of cough hypersensitivity, especially the regulation of Aδ fiber excitability by C fibers. Furthermore, the central mechanisms involved cough reflex are discussed in relation to central acting antitussives.

Effect of TNF-α, IL-2, IL-5 and IL-6 on Rat Tracheal and Bronchial Smooth Muscle Contractions

Effect of TNF-α, IL-2, IL-5 and IL-6 on Rat Tracheal and Bronchial Smooth Muscle Contractions

Integration of transcriptomics and system pharmacology to reveal the therapeutic mechanism underlying Qingfei Xiaoyan Wan to treat allergic asthma

Ethnopharmacological relevanceAsthma is a chronic inflammatory disease, characterized by airway inflammation, hyperresponsiveness, and bronchial smooth muscle contraction. Qingfei Xiaoyan Wan (QFXYW), a traditional Chinese formula, has been shown to exert anti-asthma effects and immune response in multiple diseases. Aim of this studyIn this study, we evaluated the therapeutic mechanism of QFXYW in the suppression of allergic asthma by integrating of transcriptomics and system pharmacology. Materials and methodsBALB/c mice were sensitized with ovalbumin (OVA) to establish the allergic asthma model, and its success was confirmed with behavioral observations. Lung histopathological analysis, inflammatory pathology scores, transcription factors were used to evaluate the effects of QFXYW on allergic asthma. The therapeutic mechanism of QFXYW in treating allergic asthma through integrated transcriptomics and system pharmacology was then determined: hub genes were screened out by topological analysis and functional enrichment analysis were performed to identify key signaling pathway. Subsequently, quantitative RP-PCR and protein array were performed to detect the mRNA of hub genes and to predict the key pathway in OVA-induced allergic asthma, respectively. ResultsOur results demonstrated that QFXYW could significantly attenuate inflammatory cell infiltration, mucus secretion, and epithelial damage. The transcriptomics analysis found the six hub genes with the highest values- CXCL10, CXCL2, CXCL1, IL-6, CCL-5, and CCL-4 were screened out. Functional enrichment analysis showed that the differentially expressed genes (DEGs) were mainly enriched in the inflammatory response and cytokine signaling pathway. Moreover, the quantitative RT-PCR verification experiment found the CXCL2 and CXCL1 were significantly suppressed after treatment with QFXYW. The results of protein array showed that QFXYW inhibited the multi-cytokines of OVA-induced allergic asthma via cytokine signaling pathway. ConclusionsQFXYW may have mediated OVA-induced allergic asthma mainly through the hub genes CXCL2, CXCL1, and the cytokine signaling pathway. This finding will offer a novel strategy to explore effective and safe mechanism of Traditional Chinese Medicine (TCM) formula to treat allergic asthma.

Increased Gene expression of CCL2/CCR2 axis in bronchial smooth muscles of allergen-challenged mice

PurposeAugmented bronchial smooth muscle (BSM) contraction is a cause of airway hyperresponsiveness (AHR) in asthma. Increasing evidence suggest that C-C motif chemokine 2 (CCL2) modulates smooth muscle contractility by activating its binding partner C-C chemokine receptor type 2 (CCR2). In the present study, changes in the gene expression of CCL2/CCR2 axis were determined in the BSMs of a murine model of allergic asthma. Materials and methodsThe ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, total RNAs of the main BSM tissues and bronchoalveolar lavage fluids (BALFs) were obtained. ResultsOur published microarray data (GEO accession No. GSE116504) detected changes in gene expression associated with the chemokine signaling pathway (KEGG Map ID: 04062) in BSMs of mice with AHR induced by antigen exposure. Among them, quantitative RT-PCR analyses showed significant increase in mRNA expression of Ccl2 and Ccr2. Analysis of BALFs also revealed a significant increase in Ccl2 protein in the airways of the diseased animals. ConclusionIt is thus possible that, in association with the AHR, the CCL2/CCR2 axis is enhanced in the airways of allergic bronchial asthma.

Antitussive effect of a magnesium infusion during anesthetic emergence in patients with double-lumen endotracheal tube: a randomized controlled trial.

BackgroundA double-lumen endotracheal tube (DLT) inserted into the bronchus can stimulate the respiratory tracts, causing coughing. Opioids have been introduced to prevent emergence cough. However, the administration of a significant opioid dose at the end of surgery may result in undesirable events. Magnesium, common intracellular ion, suppress bronchial smooth muscle contraction and have antitussive effect. We investigated the antitussive effects of a magnesium infusion during anesthetic emergence in patients who underwent thoracic surgery requiring one-lung ventilation (OLV) anesthesia with a DLT.MethodsOne-hundred forty patients undergoing OLV anesthesia with a DLT were enrolled in this prospective, randomized double-blinded trial. In combination with a low dose of remifentanil, patients were randomly allocated to receive either magnesium sulphate (infusion of 15 mg/kg/hour after a single bolus of 30 mg/kg) or normal saline during the operation and emergence. Primary outcomes were the severity and incidence of cough during emergence.ResultsThe severity of cough was assessed by the cough severity grading score: 0, no cough; 1, single cough; 2, cough persistence <5 seconds; 3, cough persistence ≥5 seconds. There was a significant difference in the severity score of cough between the groups [median (IQR): 2 (0 to 3) in control group vs. 0 (0 to 1) in magnesium group, P=0.003]. However, there was no significant difference in the overall incidence of cough between both groups [42 (64.6%) in control group vs. 31 (47.7%) in magnesium group, P=0.077].ConclusionsMagnesium attenuated the severity of cough during emergence after OLV anesthesia using a DLT without adverse events.

Mechanisms, diagnosis and management of eosinophilic asthma

Asthma is a common chronic airway disease affecting about 334 million people worldwide, and up to 10% of asthma patients have severe asthma, which may be uncontrolled despite high doses of the standard treatment modifiers and may require the use of chronic oral corticosteroids. It is the most common chronic disease in children in the developed countries. Asthmamanifests as reversible airflow obstruction, due to airway inflammation, bronchial smooth muscle contraction, increased mucus secretion, vascular engorgement, mucosal oedema, and airway hyper responsiveness, which leads to airflow obstruction and symptoms of asthma. Eosinophilic asthma is a phenotype of asthma that is usually very severe and persistent, with frequent exacerbations. It is usually observed in adult asthmatic patients, although it may occur in children. It is characterized by the presence of high levels of eosinophils, and CD+4 Th2 cells in the lungs and airways, which can be demonstrated by a raised eosinophil count in blood, and induced sputum or bronchial biopsy. It is managed in a similar stepwise treatment for childhood-onset asthma, but some of the patients with eosinophilic asthma do not respond to this standard treatment including inhaled or oral corticosteroids. The logical approach to treat corticosteroid-refractory asthma is to target the eosinophilic interleukins which cause airway inflammation using monoclonal antibodies to block their activity on the eosinophils, and Th2 cells. Currently, the following monoclonal antibodies are used in the treatment of eosinophilic asthma: IgE antibody such as omalizumab, or interleukin receptor 5, or 4, and 13 antagonists, such mepolizumab, reslizumab, and dupilumab. These novel agents have proved to be very useful in relieving the symptoms, and in improving the forced expired volume in one second (FEV1), and in reducing exacerbations. They are also steroid-sparing agents, and improve the quality of lifein this debilitating phenotype of asthma.

Non-coding RNAs and bronchial smooth muscle hyperresponsiveness in allergic bronchial asthma

Non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play important roles in normal and diseased cell functions. A small GTPase RhoA is a key protein of bronchial smooth muscle (BSM) contraction, and an up-regulation of RhoA has been demonstrated in BSMs of experimental asthma. Our previous study also demonstrated that RhoA translation was controlled by a miRNA, miR-133a, in BSMs. In human BSM cells (hBSMCs), an up-regulation of RhoA was observed when the function of endogenous miR-133a was inhibited by its antagomir. Treatment of hBSMCs with interleukin-13 (IL-13) caused an up-regulation of RhoA and a down-regulation of miR-133a. In a murine experimental asthma, increased expression of IL-13 and RhoA and the BSM hyperresponsiveness were observed. Interestingly, the level of miR-133a was significantly decreased in BSMs of the diseased animals. These findings suggest that RhoA expression is negatively regulated by miR-133a in BSMs, and that the miR-133a down-regulation causes an up-regulation of RhoA, resulting in an augmentation of the contraction. Recent studies also revealed an inhibitory effect of lncRNA Malat1 on the miR-133a function. Thus, lncRNAs/miRNAs might be key regulators of BSM hyperresponsiveness, and provide us a new insight into the treatment of airway hyperresponsiveness in asthmatics.

Non-coding RNAs and bronchial smooth muscle hyperresponsiveness in allergic bronchial asthma

Non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play important roles in normal and diseased cell functions. A small GTPase RhoA is a key protein of bronchial smooth muscle (BSM) contraction, and an up-regulation of RhoA has been demonstrated in BSMs of experimental asthma. Our previous study also demonstrated that RhoA translation was controlled by a miRNA, miR-133a, in BSMs. In human BSM cells (hBSMCs), an up-regulation of RhoA was observed when the function of endogenous miR-133a was inhibited by its antagomir. Treatment of hBSMCs with interleukin-13 (IL-13) caused an up-regulation of RhoA and a down-regulation of miR-133a. In a murine experimental asthma, increased expression of IL-13 and RhoA and the BSM hyperresponsiveness were observed. Interestingly, the level of miR-133a was significantly decreased in BSMs of the diseased animals. These findings suggest that RhoA expression is negatively regulated by miR-133a in BSMs, and that the miR-133a down-regulation causes an up-regulation of RhoA, resulting in an augmentation of the contraction. Recent studies also revealed an inhibitory effect of lncRNA Malat1 on the miR-133a function. Thus, lncRNAs/miRNAs might be key regulators of BSM hyperresponsiveness, and provide us a new insight into the treatment of airway hyperresponsiveness in asthmatics.

Anaphylaxis.

Anaphylaxis is a sudden onset, immediate reaction that implies a risk of death. Think of a "rule of 2s" for anaphylaxis, which implies that reactions usually begin within 2 minutes to 2 hours after injection, infusion, ingestion, contact, or inhalation. Fatalities can be from asphyxiation from laryngeal or oropharyngeal swelling, collapse from hypotensive shock, cardiac arrest, or acute severe bronchoconstriction that causes respiratory failure and arrest. When there is activation of mast cells and basophils in anaphylaxis, chemical mediators are detectable. The preformed mediators from mast cells include histamine, tryptase, carboxypeptidase A, and proteoglycans (heparin, chondroitin sulfates). Newly synthesized mediators include prostaglandin D₂, leukotriene D₄, and platelet activating factor. Crucial actions of the mediators include an abrupt increase in vascular permeability, vascular smooth muscle relaxation, and bronchial smooth muscle contraction. Anaphylaxis can be classified into immunologic, nonimmunologic, or idiopathic based on the associated mechanism. For example, immunologic causes of anaphylaxis are those mediated by immunoglobulin E (IgE) antibodies acting through the FcεR I (foods, insect venom, 32 β-lactam antibiotics), whereas non-IgE immunologic anaphylaxis is mediated without the presence of anti-allergen IgE antibodies or via FcεRI activation (radiographic contrast material). Nonimmunologic anaphylaxis involves mast cell mediator release such as occurs with exercise or with cold temperature exposure, or from medications such as opioids or vancomycin. Idiopathic anaphylaxis involves mast cell activation (acutely elevated urine histamine or serum tryptase) and activated lymphocytes. Because anaphylaxis is a medical emergency, the drug of choice is epinephrine, not H1 antihistamines or H₂ receptor antagonists.

Increased Rac1 Activation in the Enhanced Carbachol-Induced Bronchial Smooth Muscle Contraction of Repeatedly Antigen-Challenged Mice.

Recently, we demonstrated that Rac1 upregulation is involved in augmented bronchial smooth muscle (BSM) contractions of antigen-challenged mice. However, change in G protein-coupled receptor (GPCR)-induced Rac1 activation remains unknown in BSMs of repeatedly antigen-challenged (Chal.) mice. We here examined carbachol (CCh)-induced Rac1 activation in BSMs of Chal. mice. Gene expression levels of both Rac1 and Rac-guanine nucleotide exchange factors (GEFs), such as Tiam1 and Trio, were increased in BSMs of Chal. mice. Furthermore, CCh-induced Rac1 activation was inhibited by pretreatment with Rac1-GEF inhibitor NSC23766 and Rac1 inhibitor EHT1864 in BSMs of sensitized-control (S.C.) and Chal. mice. Compared with S.C. mice, CCh-induced Rac1 activation was increased in BSMs of Chal. mice. In conclusion, we reported that increased CCh-induced Rac1 activation via Tiam1 and Trio upregulation, in addition to upregulate Rac1, may be involved in increased CCh-induced BSM contractions in Chal. mice.

The leukotriene receptors as therapeutic targets of inflammatory diseases.

Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and the cysteinyl LTs (CysLTs; LTC4, LTD4 and LTE4), all of which are involved in both acute and chronic inflammation. We and other groups identified a high-affinity LTB4 receptor, BLT1; the LTC4 and LTD4 receptors, CysLT1 and CysLT2; and the LTE4 receptor, GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis and phagocytosis of neutrophils, whereas CysLT1 and CysLT2 signaling induces airway inflammation by increasing vascular permeability and the contraction of bronchial smooth muscle. Recently, we and other groups suggested that the LTB4-BLT1 axis and the cysteinyl LTs-CysLT1/2 axis are involved in chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer and age-related macular degeneration using animal models for disease and gene knockout mice. This review describes the classical and novel functions of LTs and their receptors in several inflammatory diseases and discusses the potential clinical applications of antagonists for LT receptors and inhibitors of LT biosynthesis.

Up-regulation of Rac1 in the bronchial smooth muscle of murine experimental asthma.

There has been considerable research on the involvement of RhoA/Rho kinase signalling in smooth muscle contractions. However, only a few reports have addressed the specific role of Rac1, which is a member of the Rho GTPase superfamily. Therefore, this study investigated the role of Rac1-related pathways in bronchial smooth muscle (BSM) contractions. Bronchial rings isolated from mice were suspended in an organ bath, and the isometric contractions of circular smooth muscles were monitored. The phosphorylation of myosin light chains (MLCs) was analysed by immunoblotting. The Rac1 inhibitor EHT1864 inhibited carbachol (CCh)-induced BSM contractions, although high K+ depolarization-induced BSM contractions were not significantly attenuated by EHT1864. Moreover, high K+ - and phorbol 12,13-dibutyrate (PDBu; PKC activator)-induced contractions were not attenuated by Rac1 inhibition, whereas sodium fluoride (NaF)-induced force development was inhibited by EHT1864. The gene and protein expression of Rac1 was increased in the BSM of a murine model with antigen-induced airway hyper-responsiveness (AHR). In addition, an increased force of the BSM contractions in AHR was suppressed by EHT1864 treatment, suggesting that the up-regulation of Rac1 is involved in AHR. These findings suggest that an increase in Rac1-mediated signalling is involved in the augmented contractions of BSMs in antigen-induced AHR mice.

Prevalence of Hypomagnesaemia in Asthma Patients-A Cross-Sectional Study

Aim&#x0D; Magnesium intervenes in calcium transport mechanisms and intracellular phosphorylation reactions and so, it constitutes an important determinant of the contraction and relaxation state of bronchial smooth muscle. Present study was performed with an aim to know the prevalence of hypomagnesaemia in asthma patients.&#x0D; Materials and Method&#x0D; Sixty patients, who were attending department of respiratory medicine with steady asthma, were arbitrarily selected. They were evaluated clinically and their serum magnesium levels were calculated, than evaluated with the serum magnesium values of sixty non-asthmatic fit controls.&#x0D; Results&#x0D; Serum magnesium value among 1.5 and 2.5mg/dl was measured standard and every value underneath 1.5 mg/dl was measured as hypomagnesaemia. A total of 60 patients is evaluated with 60 fit persons. About 87.7% patients were establishing to have hypomagnesaemia and their serum magnesium value varies between 0.71 and 1.5 mg/dl. Remaining 12.3% patients had standard serum magnesium level.&#x0D; Conclusion&#x0D; Hypomagnesaemia is additional common in steady asthmatics than non-asthmatic Patients. Statistically significant association of hypomagnesaemia was observed with sternness of asthma. Future researches are desired by huge number of patients, and measuring Mg++ levels in RBC, WBC, or muscle cell in adding to serum Mg++ and this would be extremely obliging for evaluating the consequence of hypomagnesaemia in steady asthmatic patients.

Prevalence of Hypomagnesaemia in Asthma Patients-A Cross-Sectional Study

Aim Magnesium intervenes in calcium transport mechanisms and intracellular phosphorylation reactions and so, it constitutes an important determinant of the contraction and relaxation state of bronchial smooth muscle. Present study was performed with an aim to know the prevalence of hypomagnesaemia in asthma patients. Materials and Method Sixty patients, who were attending department of respiratory medicine with steady asthma, were arbitrarily selected. They were evaluated clinically and their serum magnesium levels were calculated, than evaluated with the serum magnesium values of sixty non-asthmatic fit controls. Results Serum magnesium value among 1.5 and 2.5mg/dl was measured standard and every value underneath 1.5 mg/dl was measured as hypomagnesaemia. A total of 60 patients is evaluated with 60 fit persons. About 87.7% patients were establishing to have hypomagnesaemia and their serum magnesium value varies between 0.71 and 1.5 mg/dl. Remaining 12.3% patients had standard serum magnesium level. Conclusion Hypomagnesaemia is additional common in steady asthmatics than non-asthmatic Patients. Statistically significant association of hypomagnesaemia was observed with sternness of asthma. Future researches are desired by huge number of patients, and measuring Mg++ levels in RBC, WBC, or muscle cell in adding to serum Mg++ and this would be extremely obliging for evaluating the consequence of hypomagnesaemia in steady asthmatic patients.

The Chemical Elucidation of Slow-Reacting Substance: Bronchospasm and Beyond.

In 1860, H.H. Salter first noted the importance of bronchial smooth muscle contraction in asthma ([1][1]). Eighty years later, Kellaway et al. ([2][2]) recognized a distinctive bioactivity whose release following Ag challenge of sensitized lung elicited a contractile response that was slower in

Rac1 modulates G-protein-coupled receptor-induced bronchial smooth muscle contraction

Increasing evidence suggests a functional role of RhoA/Rho-kinase signalling as a mechanism for smooth muscle contraction; however, little is known regarding the roles of Rac1 and other members of the Rho protein family. This study aimed to examine whether Rac1 modulates bronchial smooth muscle contraction. Ring preparations of bronchi isolated from rats were suspended in an organ bath, and isometric contraction of circular smooth muscle was measured. Immunoblotting was used to examine myosin light chain phosphorylation in bronchial smooth muscle. Our results demonstrated that muscle contractions induced by carbachol (CCh) and endothelin-1 (ET-1) were inhibited by EHT1864, a selective Rac1 inhibitor, and NSC23766, a selective inhibitor of Rac1-specific guanine nucleotide exchange factors. Similarly, myosin light chain and myosin phosphatase target subunit 1 (MYPT1) at Thr853 phosphorylation induced by contractile agonist were inhibited with Rac1 inhibition. However, contractions induced by high K+, calyculin A (a potent protein phosphatase inhibitor) and K+/PDBu were not inhibited by these Rac1 inhibitors. Interestingly, NaF (a G-protein activator)-induced contractions were inhibited by EHT1864 but not by NSC23766. We next examined the effects of a trans-acting activator of transcription protein transduction domain (PTD) fusion protein with Rac1 (PTD-Rac1) on muscle contraction. The constitutively active form of PTD-Rac1 directly induced force development and contractions were abolished by EHT1864. These results suggest that Rac1, activated by G protein-coupled receptor agonists, such as CCh and ET-1, may induce myosin light chain and MYPT phosphorylation and modulate the contraction of bronchial smooth muscle.

Study of serum magnesium levels in stable chronic obstructive pulmonary disease and chronic obstructive pulmonary disease exacerbations

Introduction: When magnesium is deficient, the action of calcium is enhanced. In contrast, an excess of magnesium blocks calcium. These interactions are important to the respiratory patient because the intracellular influx of calcium causes bronchial smooth-muscle contraction. The possibility exists that magnesium deficiency contributes to pulmonary complications. Aim of this study to check whether acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with changes in serum magnesium levels. Methodology: 20 diagnosed with COPD- exacerbations and 20 with stable COPD were included in the study. The study was conducted for a period of 2 months to compare the serum magnesium levels in both groups. The samples were collected and the magnesium levels were evaluated by biochemical analysis. Results: At the end of the study 45% of the participants in the exacerbations group had serum magnesium less than 1.5 mg/dl whereas none of the participants of the stable group had magnesium values less than 1.5 mg/dl. This suggests a possible association between low serum magnesium levels and exacerbations of COPD. Conclusions: These findings indicate that pulmonary patients should be monitored routinely for magnesium deficiency. Keywords: Acute exacerbation of chronic obstructive pulmonary disease; Magnesium; Pulmonary function test

Airway hyperresponsiveness to mannitol and methacholine and exhaled nitric oxide in children with asthma

ABSTRACTObjective: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation, and obstruction. AHR to stimuli that indirectly cause bronchial smooth muscle (BSM) contractions via release of endogenous mediators is thought to better reflect airway inflammation than AHR to stimuli that act directly on BSM. Fractional exhaled nitric oxide (FeNO) is a useful parameter for noninvasive clinical airway inflammation assessments. Accordingly, this study aimed to examine the relationships of mannitol and methacholine challenge test outcomes with FeNO and the influence of inhaled corticosteroid treatment in children with asthma. Methods: One hundred thirty-four asthmatic children (89 males; ages: 5–17 years, median: 9 years) underwent spirometry, FeNO measurement, serum total/specific IgE testing, and blood eosinophil count. All subjects were challenged with mannitol dry powder (MDP; AridolH, Pharmaxis, Australia) and methacholine at 7-day intervals. Data of steroid-treated and steroid-naïve children were compared. Results: Positive responses to MDP and methacholine challenge tests were observed in 74.6% and 67.2% of total subject group, respectively, and 72 children had positive response to both challenge tests. The median FeNO level, response-dose ratio (RDR) of PC20 methacholine, and RDR of PD15 MDP were significantly higher in the steroid-treated group than in the steroid-naïve group (p < 0.001, 0.226, and 0.004, respectively). FeNO levels associated significantly with PD15 MDP and RDR PD15 MDP in total subject populations (p = 0.016 and 0.003, respectively); however, a significant correlation between FeNO and RDR PD15 MDP was observed only in the steroid-naïve group. Conclusions: Compared with AHR to methacholine, AHR to MDP more closely reflected the level of FeNO in steroid-naïve asthmatic children.

Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma.

Airway hyperresponsiveness (AHR) and inflammation are key pathophysiological features of asthma. Enhanced contraction of bronchial smooth muscle (BSM) is one of the causes of the AHR. It is thus important for development of asthma therapy to understand the change in the contractile signaling of airway smooth muscle cells associated with the AHR. In addition to the Ca2+-mediated phosphorylation of myosin light chain (MLC), contractile agonists also enhance MLC phosphorylation level, Ca2+-independently, by inactivating MLC phosphatase (MLCP), called Ca2+ sensitization of contraction, in smooth muscle cells including airways. To date, involvements of RhoA/ROCKs and PKC/Ppp1r14a (also called as CPI-17) pathways in the Ca2+ sensitization have been identified. Our previous studies revealed that the agonist-induced Ca2+ sensitization of contraction is markedly augmented in BSMs of animal models of allergen-induced AHR. In BSMs of these animal models, the expression of RhoA and CPI-17 proteins were significantly increased, indicating that both the Ca2+ sensitizing pathways are augmented. Interestingly, incubation of BSM cells with asthma-associated cytokines, such as interleukin-13 (IL-13), IL-17, and tumor necrosis factor-α (TNF-α), caused up-regulations of RhoA and CPI-17 in BSM cells of naive animals and cultured human BSM cells. In addition to the transcription factors such as STAT6 and NF-κB activated by these inflammatory cytokines, an involvement of down-regulation of miR-133a, a microRNA that negatively regulates RhoA translation, has also been suggested in the IL-13- and IL-17-induced up-regulation of RhoA. Thus, the Ca2+ sensitizing pathways and the cytokine-mediated signaling including microRNAs in BSMs might be potential targets for treatment of allergic asthma, especially the AHR.