Exposure to high altitudes generates a decrease in the partial pressure of oxygen, triggering a hypobaric hypoxic condition. This condition produces pathophysiologic alterations in an organism. In the lung, one of the principal responses to hypoxia is the development of hypoxic pulmonary vasoconstriction (HPV), which improves gas exchange. However, when HPV is exacerbated, it induces high-altitude pulmonary hypertension (HAPH). Another important illness in hypobaric hypoxia is high-altitude pulmonary edema (HAPE), which occurs under acute exposure. Several studies have shown that inflammatory processes are activated in high-altitude illnesses, highlighting the importance of the crosstalk between hypoxia and inflammation. The aim of this review is to determine the inflammatory pathways involved in hypobaric hypoxia, to investigate the key role of inflammation in lung pathologies, such as HAPH and HAPE, and to summarize different anti-inflammatory treatment approaches for these high-altitude illnesses. In conclusion, both HAPE and HAPH show an increase in inflammatory cell infiltration (macrophages and neutrophils), cytokine levels (IL-6, TNF-α and IL-1β), chemokine levels (MCP-1), and cell adhesion molecule levels (ICAM-1 and VCAM-1), and anti-inflammatory treatments (decreasing all inflammatory components mentioned above) seem to be promising mitigation strategies for treating lung pathologies associated with high-altitude exposure.

/pdf/inflammation-in-pulmonary-hypertension-and-edema-induced-by-2l8n1dmh.pdf

Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure

Chemotherapy resistance is a major limiting factor for the extensive use of chemotherapeutic drugs in cancer treatment. Despite the large number of newly discovered medications, treatment success rates are still unsatisfactory. Programmed cell death, called apoptosis, is one of the main tissue homeostasis mechanisms that balances cell survival and death. Apoptosis can be induced through extrinsic and intrinsic pathways or repressed by inhibitor proteins. During tumor progression, homeostasis between the anti-apoptotic and pro-apoptotic regulators is disturbed and shifted towards survival through various escape mechanisms. Dysregulation of apoptosis-regulatory mediators, particularly high levels of anti-apoptotic proteins, is one of the main mechanisms by which tumor cells acquire resistance to chemo- and radiotherapy. Therefore, it is important to restore apoptosis in the chemo- and radiotherapy resistant tumor cells. In this chapter, we summarize general chemotherapy resistance mechanisms, discuss the role of extrinsic and intrinsic pathways in chemoresistance, and review the current experimental strategies to overcome chemotherapy resistance targeting the apoptotic pathways. 

/pdf/targeting-apoptosis-to-overcome-chemotherapy-resistance-3gshmtrl.pdf

Targeting Apoptosis to Overcome Chemotherapy Resistance

Inflammatory organ injury and sepsis have profound impacts on the morbidity and mortality of surgical and critical care patients. MicroRNAs are small RNAs composed of 20–25 nucleotides that have a significant contribution to gene regulation. MicroRNA-147 (miR-147), in particular, has been shown to have an emerging role in different physiological functions such as cell cycle regulation and inflammatory responses. However, animal model systems to study tissue-specific functions of miR-147 during inflammatory conditions in vivo are lacking. In the present study, we characterize miR-147 expression in different organs and cell types. Next, we generated a transgenic mouse line with a floxed miR-147 gene. Subsequently, we used this mouse line to generate mice with whole-body deletion of miR-147 (miR-147 −/−) by crossing “floxed” miR-147 mice with transgenic mice expressing Cre recombinase in all tissues (CMVcre mice). Systematic analysis of miR-147 −/− mice demonstrates normal growth, development, and off-spring. In addition, deletion of the target gene in different organs was successful at baseline or during inflammation, including the heart, intestine, stomach, liver, spleen, bone marrow, lungs, kidneys, or stomach. Moreover, miR-147 −/− mice have identical baseline inflammatory gene expression compared to C57BL/6 mice, except elevated IL-6 expression in the spleen (7.5 fold, p < 0.05). Taken together, our data show the successful development of a transgenic animal model for tissue and cell-specific deletion of miR-147 that can be used to study the functional roles of miR-147 during inflammatory organ injury.

/pdf/characterization-of-a-murine-model-system-to-study-microrna-49i3zkd52z.pdf

Characterization of a Murine Model System to Study MicroRNA-147 During Inflammatory Organ Injury.

Abstract Objective: To establish a novel mouse model of acute myocardial injury induced by hypobaric hypoxia and improve the relevant evaluation system. Methods: Using the plateau simulator made by our institute (which has e Chinese invention patent, patent number: ZL 2021 1 1517241. X), Babl/c mice were continuously exposed to the extreme altitude, low pressure and hypoxia environment for 0h-216h. PET/CT was used to evaluate the metabolic function of myocardial cells in mice by injecting 18 F-FDG in vivo. the changes of cardiac function and morphology was observed in mice by cardiac ultrasound. FITC-BSA was injected into the tail vein to verify the leakage function of blood vessels in the heart tissue of mice. HE staining, Masson staining, CD163 and CD34 immunohistochemical staining get used to verify the degree of myocardial injury, fibrosis, inflammatory cell infiltration and angiogenesis in mice. Results: The myocardial metabolic function of Babl/c mice in hypobaric hypoxia environment was enhanced at the early stage of exposure, and then gradually weakened. With the extension of time, the heart rate gradually accelerated, the myocardial morphology changed significantly, the myocardial pathological changes and damage gradually increased, the role of vascular leakage gradually increased, the infiltration of inflammatory cells increased, and the myocardial fibrosis increased significantly. 

Establishment and validation of acute myocardial injury model in mice with hypobaric hypoxia at extreme altitude

Huangqi Baihe Granules (HQBHG) are a modified formulation based on the traditional recipe "Huangqi Baihe porridge" and the Dunhuang medical prescription "Cistanche Cistanche Soup." The Herbal medicine moistens the lungs and tones the kidneys in addition to replenishing Qi and feeding Yin, making it an ideal choice for enhancing adaptability to high-altitude hypoxic environments.The purpose of this study was to examine a potential molecular mechanism for the treatment and prevention of hypoxic acute lung injury (ALI) in rats using Huangqi Baihe Granules.The HCP-III laboratory animal low-pressure simulation chamber was utilized to simulate high-altitude environmental exposure and establish an ALI model in rats. The severity of lung damage was evaluated using a battery of tests that included spirometry, a wet/dry lung ratio, H&E staining, and transmission electron microscopy. Using immunofluorescence, the amount of reactive oxygen species (ROS) in lung tissue was determined. Superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and myeloperoxidase (MPO) levels in lung tissue were determined using this kit. Serum levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta), and antiinflammatory cytokines like interleukin-10 (IL-10) were measured using an enzyme-linked immunosorbent assay kit. Gene expression changes in lung tissue were identified using transcriptomics, and the relative expression of proteins and mRNA involved in the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB p65)/Nod-like receptor protein 3 (NLRP3) pathway were determined using western blotting and quantitative real-time PCR.HQBHG was shown to enhance lung function considerably, decrease the wet/dry ratio of the lungs, attenuate lung tissue damage, suppress ROS and MDA formation, and increase SOD activity and GSH expression. The research also demonstrated that HQBHG inhibited the activation of the TLR4/NF-κB p65/NLPR3 signaling pathway in lung tissue, reducing the release of downstream pro-inflammatory cytokines.HQBHG exhibits potential therapeutic effects against ALI induced by altitude hypoxia through suppressing oxidative stress and inflammatory response. This suggests it may be a novel drug for treating and preventing ALI. 

Huangqi Baihe Granules alleviate hypobaric hypoxia-induced acute lung injury in rats by suppressing oxidative stress and the TLR4/NF-κB/NLRP3 inflammatory pathway.

Background: This study aimed to explore the effects of netrin-1 on hypobaric hypoxia-induced lung injury in mice. Methods: We exposed 6–8-week-old C57BL/6 mice to hypobaric stress at 340 m...

Netrin-1 Dampens Hypobaric Hypoxia-Induced Lung Injury in Mice.

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Netrin-1 Dampens Hypobaric Hypoxia-Induced Lung Injury in Mice.