The Impact of Tezepelumab in Uncontrolled Severe Asthma: A Systematic Review of Randomized Controlled Trials.

Asthma, a chronic illness, is characterized by inflammation and airway constriction. Uncontrolled severe asthma is related to poor quality of life and increased utilization of health resources. Conventional treatments are associated with a significant amount of adverse effects. Recent years have seen the identification of various molecular effectors and signaling pathways as interesting targets for the biological therapy of severe asthma that is resistant to current therapies. Because they only target some downstream components of the inflammatory response in asthma, leaving other components unaffected, current biologic treatments only lower the exacerbation rate by 50%. If we focus on the upstream mediators of the inflammatory response in asthma, it might have a greater effect and be more efficient. Tezepelumab is a human monoclonal IgG2 antibody that specifically binds to thymic stromal lymphopoietin (TSLP) at the level of its TSLPR (thymic stromal lymphopoietin receptor) binding site, inhibiting the interaction between human TSLP and TSLPR. It is being used to treat the cytokines on the respiratory epithelial layer known as "alarmins." It is the only biologic drug available for treating severe uncontrolled asthma, despite limitations in biomarker and phenotype. In light of recent developments, the lack of knowledge on tezepelumab prompts us to publish a comprehensive systematic review. We discovered that regardless of blood eosinophil level and fractional exhaled nitric oxide levels, tezepelumab dramatically lowers asthma exacerbation in patients with severe uncontrolled asthma when compared to placebo. Tezepelumab also lessens patients' demand for healthcare resources while improving clinical indicators of lung function, health-related quality of life, and asthma management in patients. Tezepelumab plays a role in enhancing pre-bronchodilator FEV1 and lowering blood eosinophil count and fractional exhaled nitric oxide in patients with or without chronic allergies (FeNO). There have been no reports of fatalities or severe adverse events connected to tezepelumab.

Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A).

OBJECTIVE: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. CONCLUSIONS: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.

Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. OBJECTIVE: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. METHODS AND RESULTS: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. CONCLUSIONS: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.