High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hypertension under hypobaric hypoxia and proposes updates to pharmacological treatments to mitigate the pathological changes in PASMCs under such conditions. In general, PASMCs exposed to hypobaric hypoxia undergo oxidative stress mediated by Nox4, inflammation mediated by increases in interleukin-6 levels and inflammatory cell infiltration, and activation of the protein kinase ERK1/2, which lead to the proliferation of PASMCs and contribute to the development of hypobaric hypoxia-induced pulmonary hypertension.

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Oxidative Stress, Kinase Activation, and Inflammatory Pathways Involved in Effects on Smooth Muscle Cells During Pulmonary Artery Hypertension Under Hypobaric Hypoxia Exposure.

Pulmonary macrophages and their different roles in health and disease.

Iron oxide nanoparticles (Fe2O3 NPs) is the main component of air pollution particles in urban rail transit environment. People are more exposed to Fe2O3 NPs, however, the studies on relationship between Fe2O3 NPs and respiratory health are limited. In the present study, acute airway inflammation caused by Fe2O3 NPs and its possible mechanism were investigated. BALB/c mice were intratracheally challenged with different concentrations of Fe2O3 NPs. Fe2O3 NPs induced bronchial epithelial barrier function damage, infiltration of neutrophils and lymphocytes into the airway submucosa, secretion of mucus in the airway epithelium and elevated expression of eosinophil major basic protein (EMBP) in lungs. Compared with the control group, Fe2O3 NPs increased eosinophils by 20 times in bronchoalveolar lavage fluid (BALF), and markedly increased eosinophils related cytokines and chemokines, including interleukin (IL) ‐5, IL‐33, thymic stromal lymphopoietin (TSLP), monocyte chemotactic protein (MCP)‐3, eotaxin, tumor necrosis factor (TNF)‐α, keratinocyte chemoattractant (KC). Furthermore, Fe2O3 NPs up‐regulated levels of IL‐5, MCP‐3, eotaxin, and KC in serum. In vitro studies showed that Fe2O3 NPs increased the genes and proteins expression of Toll‐like receptors (TLR)‐2, TLR4, TNF receptor associated factor 6 (TRAF6), myeloid differentiation factor 88 (MyD88), nuclear factor (NF)‐κB, and TNF‐α in RAW267.4 cells. The downstream inflammatory cytokine protein expression and release such as TNF‐α was significantly decreased after using TLR2/TLR4 inhibitor OxPAPC, but not MyD88 inhibitor ST2825. These results suggest that TLR2 and TLR4 played important role in Fe2O3 NPs inducing acute eosinophilic airway inflammation in the murine lung.

Acute iron oxide nanoparticles exposure induced murine eosinophilic airway inflammation via TLR2 and TLR4 signaling

The bioactive components of Canavalia lineata (Thunb.) DC pods were investigated using bioactivity-guided isolation, and the chemical structures of flavonoids 1–3, isoflavonoid derivatives 4–11, and phenolic compounds 12 and 13 were identified by comparing NMR, MS, and CD spectral data with previously reported spectroscopic data. Compounds 1–13 were evaluated for their anti-inflammatory effects on LPS-stimulated RAW264.7 macrophages. Among these compounds, the isoflavonoid derivative cajanin (7) exhibited the most potent anti-inflammatory activity (IC50 of NO = 19.38 ± 0.05 µM; IC50 of IL-6 = 7.78 ± 0.04 µM; IC50 of TNF-α = 26.82 ± 0.11 µM), exerting its anti-inflammatory effects by suppressing the activation and nuclear translocation of the transcription factor NF-κB by phosphorylating IκB and p65. These results suggested that cajanin (7) may be a potential candidate for improving the treatment of inflammatory diseases.

/pdf/anti-inflammatory-activity-of-cajanin-an-isoflavonoid-1bld5ko6.pdf

Anti-Inflammatory Activity of Cajanin, an Isoflavonoid Derivative Isolated from Canavalia lineata Pods

Recent advancements and application of in vitro models for predicting inhalation toxicity in humans

Callicarpa japonica Thunb. ameliorates allergic airway inflammation by suppressing NF-κB activation and upregulating HO-1 expression.

A number of species of the genus Trichilia (Meliaceae) exhibit anti-inflammatory effects. However, the effect of Trichilia martiana C. DC. (TM) on lipopolysaccharide (LPS)-induced inflammation has not, to the best of our knowledge, yet been determined. Therefore, in the present study, the anti-inflammatory effect of TM on LPS-stimulated RAW264.7 macrophages was evaluated. The ethanol extract of TM (TMEE) significantly inhibited LPS-induced nitric oxide (NO), prostaglandin 2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). TMEE also reduced the levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. The upregulation of mitogen-activated protein kinases (MAPKs) and NF-κB activation was revealed to be downregulated following TMEE pretreatment. Furthermore, TMEE was indicated to lead to the nucleus translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1). In H292 airway epithelial cells, the pretreatment of TMEE significantly downregulated the production of LPS-stimulated IL-1β, and TMEE was indicated to increase the expression of HO-1. In animal models exhibiting LPS-induced acute lung injury (ALI), treatment with TMEE reduced the levels of macrophages influx and TNF-α production in the bronchoalveolar lavage fluid (BALF) of ALI mice. Additionally, TMEE significantly downregulated the activation of ERK, JNK and IκB, and upregulated the expression of HO-1 in the lungs of ALI mice. In conclusion, the results of the current study demonstrated that TMEE could exert a regulatory role in the prevention or treatment of the endotoxin-mediated inflammatory response.

https://koreascience.or.kr:443/article/JAKO202034965719518.pdf

The Anti-Inflammatory Effect of Trichilia martiana C. DC. in the Lipopolysaccharide-Stimulated Inflammatory Response in Macrophages and Airway Epithelial Cells and in LPS-Challenged Mice.

Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.

https://www.mdpi.com/2073-4409/10/4/897/pdf

Jae-Hong Min

Papers

Callicarpa japonica Thunb. ameliorates allergic airway inflammation by suppressing NF-κB activation and upregulating HO-1 expression.

The Anti-Inflammatory Effect of Trichilia martiana C. DC. in the Lipopolysaccharide-Stimulated Inflammatory Response in Macrophages and Airway Epithelial Cells and in LPS-Challenged Mice.

The Role of Macrophages in the Development of Acute and Chronic Inflammatory Lung Diseases.