A narrative review of research advances in hypoxic pulmonary hypertension.

Background and Objective: Hypoxic pulmonary hypertension (HPH) is a pathological syndrome characterized by pulmonary vasoconstriction and pulmonary vascular remodeling caused by hypoxia, which eventually leads to right heart failure or death. There are 2 stages of onset of HPH: hypoxic pulmonary vasoconstriction (HPV) and hypoxic pulmonary vascular remodeling (HPVR). It is an important pathophysiological link in the pathogenesis of chronic obstructive pulmonary disease (COPD) and chronic mountain sickness (CMS), and its severity is closely related to the course and prognosis of COPD and CMS. However, there is a lack of systematic review on the diagnosis, pathogenesis and treatment of HPH. The objective of this paper is to review the diagnosis, pathogenesis, treatment of HPH. Methods: In this paper, the method of literature review is adopted to obtain the information about HPH. Based on the literature, comprehensive and systematic review is made. The diagnosis, pathogenesis, treatment of HPH are summarized. Key Content and Findings: Right heart catheterization is the gold standard for diagnosing HPH. Hypoxia-inducible factor, oxidative stress, metal metabolism, ion channel, inflammatory cytokines, cell apoptosis and vascular factors are the main pathogenesis of HPH. The treatment of HPH includes long-term oxygen therapy, statins, prostaglandins, phosphodiesterase inhibitor and ET receptor antagonists. Conclusions: Although great progress has been made in the pathophysiology and molecular biology of HPH, it is still unclear which factors play a leading role in the pathogenesis of HPH, and no breakthrough has been made in the treatment of HPH. It is believed that the specific mechanism will be revealed as the research continues, and earlier diagnosis and the development of more effective targeted drugs will be the focus of future research.

The microRNA-1278/SHP-1/STAT3 pathway is involved in airway smooth muscle cell proliferation in a model of severe asthma both intracellularly and extracellularly.

This study investigated the regulatory effects of microRNA-1278 (miR-1278) on airway inflammation, airway reconstruction, and the proliferation and apoptosis of airway smooth muscle cells (ASMCs) induced by transforming growth factor ß1 (TGF-ß1). The results showed that miR-1278 was upregulated in the blood and lung tissues (LTs) of patients with asthma compared with that in healthy volunteers; miR-1278 expression was also upregulated in asthmatic mice, and miR-1278 inhibition improved the LTs of asthmatic mice. Moreover, miR-1278 inhibited inflammation in asthmatic mice and counteracted the effect of TGF-ß1 of induced proliferation and reduced apoptosis in ASMCs. DLRA indicated that miR-1278 targeted the 3'-UTR of Src-homology 2-containing phosphatase 1 (SHP-1). Furthermore, miR-1278 promoted ASMC proliferation, in which TGF-ß1 played an important role by regulating the SHP-1/STAT3 signaling pathway. In conclusion, this study showed that miR-1278 played a critical role in the processes of airway remodeling and reduction of apoptosis by targeting SHP-1.

Hypoxic stress suppresses lung tumor-secreted exosomal miR101 to activate macrophages and induce inflammation.

Hypoxia promotes inflammation in the tumor microenvironment. Although hypoxia-inducible factor 1α (HIF1α) is a master modulator of the response to hypoxia, the exact mechanisms through which HIF1α regulates the induction of inflammation remain largely unclear. Using The Cancer Genome Atlas Lung Squamous Cell Carcinoma (TCGA-LUSC) database, we divided patients with LUSC into two groups based on low or high HIF1α expression. After analyzing the differentially expressed genes in these two groups, we found that HIF1α was positively correlated with interleukin 1A (IL1A) and IL6 expression. Our in vitro study showed that hypoxic stress did not induce IL1A or IL6 expression in tumor cells or macrophages but dramatically enhanced their expression when co-cultured with tumor cells. We then investigated the effect of tumor-derived exosomes on macrophages. Our data suggested that the changes in miR101 in the tumor-derived exosomes played an important role in IL1A and IL6 expression in macrophages, although the hypoxic stress did not change the total amount of exosome secretion. The expression of miR101 in exosomes was suppressed by hypoxic stress, since depletion of HIF1α in tumor cells recovered the miR101 expression in both tumor cells and exosomes. In vitro, miRNA101 overexpression or uptake enriched exosomes by macrophages suppressed their reprogramming into a pro-inflammatory state by targeting CDK8. Injection of miR101 into xenografted tumors resulted in the suppression of tumor growth and macrophage tumor infiltration in vivo. Collectively, this study suggests that the HIF1α-dependent suppression of exosome miR101 from hypoxic tumor cells activates macrophages to induce inflammation in the tumor microenvironment.

SET knockdown attenuated phenotype modulation and calcium channel associated markers of airway smooth muscle cells in asthmatic mice.

BACKGROUND: Dysfunctional phenotype modulation and calcium channels in airway smooth muscle cells (ASMCs) are important characteristics of airway remodeling in chronic asthma. However, the mechanisms underlying these pathological processes remain unclear. SET (I2PP2A, inhibitor-2 of protein phosphatase 2A) has many significant functions and is involved in various physiological and pathological processes. This study aimed to determine the function of SET in chronic asthma. METHODS: BALB/c mice were sensitized by ovalbumin injection and repeated inhalation of ovalbumin. The Penh value was measured using the Buxco whole body plethysmography system. A short hairpin RNA of the SET gene was designed and transfected into ASMCs derived from asthmatic mice. Flow cytometry of Annexin-V/propidium iodide staining was used for evaluating cell apoptosis. Western blot was adopted to measure the expression levels of ASMCs phenotype modulation markers and calcium channel-associated proteins. RESULTS: The results showed that shRNA targeting SET significantly decreased the expression of SET, and enhanced the apoptosis of ASMCs. SET knockdown promoted the expression of contractile phenotype markers such as α-SMA (alpha smooth muscle Actin), SM-MHC (smooth muscle Myosin heavy chain), and calponin, and inhibited the expression of synthetic phenotype markers including vimentin and CD44. The expression of the calcium channel-related proteins STIM1 (Stromal interaction molecule 1) and Orai1 were also inhibited after SET knockdown. CONCLUSIONS: These data demonstrated that SET participated in the development of airway dysfunction in asthma, suggesting that the silencing of SET may be a new therapeutic target for the treatment of asthma patients.

Casticin Improves Respiratory Dysfunction and Attenuates Oxidative Stress and Inflammation via Inhibition of NF-ĸB in a Chronic Obstructive Pulmonary Disease Model of Chronic Cigarette Smoke-Exposed Rats.

OBJECTIVE: The present study was conducted to elucidate the protective effect of Casticin against chronic obstructive pulmonary disease (COPD) in rats. METHODS: The COPD in rats was induced by the controlled cigarette smoke, and CST (10, 20, and 30 mg/kg) was injected into the cigarette-smoke exposed rats. Blood was taken from the abdominal vein and centrifuged (1500×g, 4°C, 15min); plasma was collected and used for the determination of various biochemical parameters. RESULTS: The results of the study suggested that CST significantly improved the lung functions of the rats in a dose-dependent manner. It also causes a reduction of white blood cells, neutrophils, and macrophages in BALF of rats. The plasma level of leptin and C-reactive protein together with pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) were also significantly restored to near to normal in CST-treated group. In Western blot analysis, CST causes significant inhibition of the NF-ĸB and iNOS pathway. CONCLUSION: Our study demonstrated that the CST protects lungs against COPD via improving lung functions and inhibition of oxidative stress and inflammation.

Molecular biology of BPIFB1 and its advances in disease.

Bactericidal/permeability-increasing (BPI)-fold-containing family B member 1 (BPIFB1), also known as long-palate lung and nasal epithelium clone 1 (LPLUNC1), belongs to the BPI-fold-containing family, is a newly discovered natural immune protection molecule, which, having the function of bactericidal and osmotic enhancement protein domain, can respond to the external physical and chemical stimuli. The gene of BPIFB1 is located at chromosome 20q11.21-20q11.22, and contains 16 exons and 15 introns, encoding 484 amino acids. The 5' terminal of the BPIFB1 protein has a signal peptide sequence composed of 19 amino acids. BPIFB1 is abnormally expressed in nasopharyngeal carcinoma (NPC), gastric cancer, and other cancer tissues, regulate chronic infections and inflammation, indicating that it may play an important role in the development of tumors. Meanwhile, BPIFB1 has well-recognized roles in sensing and responding to Gram-negative bacteria due to its structural similarity with BPI protein and lipopolysaccharide (LPS)-binding protein, both of which are innate immune molecules with recognized roles in sensing and responding to Gram-negative bacteria, so it can regulate cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), asthma, and other respiratory diseases. In this article, we will discuss the progress of BPIFB1 in a variety of diseases and fully understand its function.

The application of proteomics in the diagnosis and treatment of bronchial asthma.

Bronchial asthma is a common chronic inflammatory disease of the airways. Although its pathogenic mechanism remains unknown, it is influenced by both genetic and environmental factors. The emergence and application of proteomic technologies can help to facilitate analysis of the changes in transcription factors, inflammatory mediators, chemokines, cytokines, and cell apoptosis-and proliferation-related proteins in the pathological processes of asthma. Proteomic technologies can unearth prospects and theoretical bases for improved understanding of the biological mechanism of asthma and effective identification of diagnostic and therapeutic targets.