The Role of Immune Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology with limited treatment options. The role of the immune system in IPF has received increasing attention. Uncontrolled immune responses drive the onset and progression of IPF. This article provides an overview of the role of innate immune cells (including macrophages, neutrophils, mast cells, eosinophils, dendritic cells, nature killer cells, nature kill cells and γδ T cells) and adaptive immune cells (including Th1 cells, Th2 cells, Th9 cells, Th17 cells, Th22 cells, cytotoxic T cells, B lymphocytes and Treg cells) in IPF. In addition, we review the current status of pharmacological treatments for IPF and new developments in immunotherapy. A deeper comprehension of the immune system's function in IPF may contribute to the development of targeted immunomodulatory therapies that can alter the course of the disease.

Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs.

BACKGROUND: Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis. METHODS: To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1ß, both of which are the primary methods for assessing pyroptosis. RESULTS: IL-18 and IL-1ß concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1ß and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs. CONCLUSIONS: Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.

A multi-responsive Au NCs@PMLE/Ca2+ antitumor hydrogel formed in situ on the interior/surface of tumors for PT imaging-guided synergistic PTT/O2-enhanced PDT effects.

At present, although phototherapy and related imaging have proven to be promising cancer diagnosis and treatment strategies, the free diffusion of photosensitizers into normal tissues can cause side effects, and the efficiency of photodynamic therapy (PDT) can also be limited by the tumor hypoxic microenvironment. Herein, we designed and prepared a new cancer nanoplatform containing Au nanoclusters (NCs)@Premna microphylla leaf extract (PMLE) with both responsiveness to near-infrared (NIR) laser irradiation and tumor microenvironment (TME) by facile redox and coordination reactions. Then, the Au NCs@PMLE/Ca2+ hydrogel was constructed in situ inside and on the surface of tumors for locoregional antitumor activity under 808 nm laser irradiation. The Au NCs@PMLE nanoplatform showed distinguished performance in killing cancer cells and alleviating tumor hypoxia by enhancing the temperature of the tumor sites and producing reactive oxygen species (ROS) under NIR irradiation as well as catalyzing hydrogen peroxide (H2O2) decomposition in TME for oxygen (O2) generation via catalase in PMLE. The ultra-small size of about 3 nm of the Au NCs in this nanoplatform was obtained using the biological molecules present in PMLE as reductants and coordination agents simultaneously, which also demonstrated the outstanding capability of photothermal (PT) imaging and photothermal therapy (PTT) towards tumors. Furthermore, the Au NCs@PMLE/Ca2+ hydrogel formed in situ through natural PMLE and intrinsic Ca2+ in TME could not only improve the biocompatibility of the nanoplatform and stability of Au NCs but was also highly concentrated around the tumor thus enhancing the therapeutic efficiency and inhibiting its migration to normal tissues, decreasing the side effects. The results of the experiments confirmed that the Au NCs@PMLE/Ca2+ hydrogel possessed PT imaging-guided NIR laser/TME-responsive synergetic cancer PTT/O2-enhanced PDT and remarkable locoregional antitumor effect for cancer therapy. This work may open a new versatile route for multi-responsive localized cancer therapeutic nanoplatforms.

The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice.

This study aims to investigate the possible mechanisms of electroacupuncture (EA) at PC6 to improve myocardial ischemia (MI) by regulating the cardiac transient outward potassium current channel (Ito). According to the random number table, the mice were divided into six groups of six mice each: control group, MI group, PC6, LU7 (Lieque-point), ST36 (Zusanli-point), and nonacupoint group. Mice in the control group were injected with saline (20 mg/kg, 24 hours interval), and the other ASIC3 -/- mice were injected subcutaneously twice with isoproterenol (ISO) (20 mg/kg, 24 hours interval). In the preexperiment, 5 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg of ISO were used, and the results showed that 5 mg/kg and 10 mg/kg of ISO both could induce acute MI, but shorter duration of sustained MI. On the other hand, an injection of 30 mg/kg can make the mice experience arrhythmia or die immediately, and EA was operated at PC6, LU7, ST36 acupoints, and nonacupoint in the mice of PC6, LU7, ST36, and nonacupoint groups, respectively, after injecting twice. Then Western blotting techniques (Western Blot) were used to analyze the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KchIP2. The results of this experiment showed that the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KChIP2 in MI group were significantly lower than those in the control group (p < 0.01). Compared with MI group, the results of PC6, LU7, and ST36 groups obviously increased (p < 0.05). Furthermore, the expressions of PC6 group were higher than LU7 group and ST36 group (p < 0.05). And electrocardiogram's T-waves showed obvious pathological changes in the MI group compared to the control group (p < 0.01). After EA, the abnormal T-waves voltage of ECG in PC6, LU7, and ST36 groups was improved (p < 0.05). In addition, the rate change of PC6 group was larger than that of both LU7 and ST36 groups (p < 0.05). But the T-waves voltage of the nonacupoint group was not significantly different than that of the MI group (p > 0.05).