Abi1 mediates airway smooth muscle cell proliferation and airway remodeling via Jak2/STAT3 signaling

Asthma is a complex pulmonary disorder with multiple pathological mechanisms. A key pathological feature of chronic asthma is airway remodeling, which is largely attributed to airway smooth muscle (ASM) hyperplasia that contributes to thickening of the airway wall and further drives asthma pathology. The cellular processes that mediate ASM cell proliferation are not completely elucidated. Using multiple approaches, we demonstrate that the adapter protein Abi1 (Abelson interactor 1) is upregulated in ∼50% of ASM cell cultures derived from patients with asthma. Loss-of-function studies demonstrate that Abi1 regulates the activation of Jak2 (Janus kinase 2) and STAT3 (signal transducers and activators of transcription 3) as well as the proliferation of both nonasthmatic and asthmatic human ASM cell cultures. These findings identify Abi1 as a molecular switch that activates Jak2 kinase and STAT3 in ASM cells and demonstrate that a dysfunctional Abi1-associated pathway contributes to the progression of asthma

Role and regulation of Abelson tyrosine kinase in Crk-associated substrate/profilin-1 interaction and airway smooth muscle contraction

Abstract Background Airway smooth muscle contraction is critical for maintenance of appropriate airway tone, and has been implicated in asthma pathogenesis. Smooth muscle contraction requires an “engine” (myosin activation) and a “transmission system” (actin cytoskeletal remodeling). However, the mechanisms that control actin remodeling in smooth muscle are not fully elucidated. The adapter protein Crk-associated substrate (CAS) regulates actin dynamics and the contraction in smooth muscle. In addition, profilin-1 (Pfn-1) and Abelson tyrosine kinase (c-Abl) are also involved in smooth muscle contraction. The interplays among CAS, Pfn-1 and c-Abl in smooth muscle have not been previously investigated. Methods The association of CAS with Pfn-1 in mouse tracheal rings was evaluated by co-immunoprecipitation. Tracheal rings from c-Abl conditional knockout mice were used to assess the roles of c-Abl in the protein-protein interaction and smooth muscle contraction. Decoy peptides were utilized to evaluate the importance of CAS/Pfn-1 coupling in smooth muscle contraction. Results Stimulation with acetylcholine (ACh) increased the interaction of CAS with Pfn-1 in smooth muscle, which was regulated by CAS tyrosine phosphorylation and c-Abl. The CAS/Pfn-1 coupling was also modified by the phosphorylation of cortactin (a protein implicated in Pfn-1 activation). In addition, ACh activation promoted the spatial redistribution of CAS and Pfn-1 in smooth muscle cells, which was reduced by c-Abl knockdown. Inhibition of CAS/Pfn-1 interaction by a decoy peptide attenuated the ACh-induced actin polymerization and contraction without affecting myosin light chain phosphorylation. Furthermore, treatment with the Src inhibitor PP2 and the actin polymerization inhibitor latrunculin A attenuated the ACh-induced c-Abl tyrosine phosphorylation (an indication of c-Abl activation). Conclusions Our results suggest a novel activation loop in airway smooth muscle: c-Abl promotes the CAS/Pfn-1 coupling and actin polymerization, which conversely facilitates c-Abl activation. The positive feedback may render c-Abl in active state after contractile stimulation

Alterations in platelet bioenergetics in Group 2 PH-HFpEF patients.

BackgroundPulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure but classified into subgroups based on disease etiology. It is established that systemic bioenergetic dysfunction contributes to the pathogenesis of pulmonary arterial hypertension classified as World Health Organization (WHO) Group 1. Consistent with this, we previously showed that platelets from Group 1 PH patients demonstrate increased glycolysis and enhanced maximal capacity for oxidative phosphorylation, which is due to increased fatty acid oxidation (FAO). However, it remains unclear whether identical mitochondrial alterations contribute to the pathology of other PH subgroups. The most prevalent subgroup of PH is WHO Group 2, which encompasses pulmonary venous hypertension secondary to left heart disease. Here, we hypothesized that platelets from Group 2 subjects show bioenergetic alteration compared to controls, and that these changes were similar to Group 1 PH patients.Method and resultsWe isolated platelets from subjects with Group 2 PH and controls (n = 20) and measured platelet bioenergetics as well as hemodynamic parameters. We demonstrate that Group 2 PH platelets do not show a change in glycolytic rate but do demonstrate enhanced maximal capacity of respiration due at least partially to increased FAO. Moreover, this enhanced maximal capacity correlates negatively with right ventricular stroke work index and is not changed by administration of inhaled nitrite, a modulator of pulmonary hemodynamics.ConclusionsThese data demonstrate that Group 2 PH subjects have altered bioenergetic function though this alteration is not identical to that of Group 1 PH. The implications of this alteration for disease pathogenesis will be discussed

Differential mitochondrial dinitrosyliron complex formation by nitrite and nitric oxide

Nitrite represents an endocrine reserve of bioavailable nitric oxide (NO) that mediates a number of physiological responses including conferral of cytoprotection after ischemia/reperfusion (I/R). It has long been known that nitrite can react with non-heme iron to form dinitrosyliron complexes (DNIC). However, it remains unclear how quickly nitrite-dependent DNIC form in vivo, whether formation kinetics differ from that of NO-dependent DNIC, and whether DNIC play a role in the cytoprotective effects of nitrite. Here we demonstrate that chronic but not acute nitrite supplementation increases DNIC concentration in the liver and kidney of mice. Although DNIC have been purported to have antioxidant properties, we show that the accumulation of DNIC in vivo is not associated with nitrite-dependent cytoprotection after hepatic I/R. Further, our data in an isolated mitochondrial model of anoxia/reoxygenation show that while NO and nitrite demonstrate similar S-nitrosothiol formation kinetics, DNIC formation is significantly greater with NO and associated with mitochondrial dysfunction as well as inhibition of aconitase activity. These data are the first to directly compare mitochondrial DNIC formation by NO and nitrite. This study suggests that nitrite-dependent DNIC formation is a physiological consequence of dietary nitrite. The data presented herein implicate mitochondrial DNIC formation as a potential mechanism underlying the differential cytoprotective effects of nitrite and NO after I/R, and suggest that DNIC formation is potentially responsible for the cytotoxic effects observed at high NO concentrations

The "3T's" road map to transform US health care - The "how" of high-quality care

BackgroundPulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure but classified into subgroups based on disease etiology. It is established that systemic bioenergetic dysfunction contributes to the pathogenesis of pulmonary arterial hypertension classified as World Health Organization (WHO) Group 1. Consistent with this, we previously showed that platelets from Group 1 PH patients demonstrate increased glycolysis and enhanced maximal capacity for oxidative phosphorylation, which is due to increased fatty acid oxidation (FAO). However, it remains unclear whether identical mitochondrial alterations contribute to the pathology of other PH subgroups. The most prevalent subgroup of PH is WHO Group 2, which encompasses pulmonary venous hypertension secondary to left heart disease. Here, we hypothesized that platelets from Group 2 subjects show bioenergetic alteration compared to controls, and that these changes were similar to Group 1 PH patients.Method and resultsWe isolated platelets from subjects with Group 2 PH and controls (n = 20) and measured platelet bioenergetics as well as hemodynamic parameters. We demonstrate that Group 2 PH platelets do not show a change in glycolytic rate but do demonstrate enhanced maximal capacity of respiration due at least partially to increased FAO. Moreover, this enhanced maximal capacity correlates negatively with right ventricular stroke work index and is not changed by administration of inhaled nitrite, a modulator of pulmonary hemodynamics.ConclusionsThese data demonstrate that Group 2 PH subjects have altered bioenergetic function though this alteration is not identical to that of Group 1 PH. The implications of this alteration for disease pathogenesis will be discussed

Preparation and Photocatalytic Properties of a Bagasse Cellulose-Supported Nano-TiO2 Photocatalytic-Coupled Microbial Carrier

Intimate coupling of photocatalysis and biodegradation (ICPB) has shown promise in removing unwanted organic compounds from water. In this study, bagasse cellulose titanium dioxide composite carrier (SBC-TiO2) was prepared by low-temperature foaming methods. The optimum preparation conditions, material characterization and photocatalytic performance of the composite carrier were then explored. By conducting a single factor test, we found that bagasse cellulose with a mass fraction of 4%, a polyvinyl alcohol solution (PVA) with a mass fraction of 5% and 20 g of a pore-forming agent were optimum conditions for the composite carrier. Under these conditions, good wet density, porosity, water absorption and retention could be realized. Scanning electron microscopy (SEM) results showed that the composite carrier exhibited good biologic adhesion. X-ray spectroscopy (EDS) results confirmed the successful incorporation of nano-TiO2 dioxide into the composite carrier. When the mass concentration of methylene blue (MB) was 10 mg L−1 at 200 mL, 2 g of the composite carrier was added and the initial pH value of the reaction was maintained at 6, the catalytic effect was best under these conditions and the degradation rate reached 78.91% after 6 h. The method of preparing the composite carrier can aid in the degradation of hard-to-degrade organic compounds via ICPB. These results provide a solid platform for technical research and development in the field of wastewater treatment