Biomass-related PM2.5 induces mitochondrial fragmentation and dysfunction in human airway epithelial cells.

The use of biomass for cooking and heating is considered an important factor associated with chronic obstructive pulmonary disease (COPD), but few studies have previously addressed its underlying mechanisms. Therefore, this research aimed to evaluate the effects of biomass-related PM2.5 (BRPM2.5) exposure on 16HBE human airway epithelial cells and in mice with regard to mitochondrial dysfunction. Our study indicated that BRPM2.5 exposure of 16HBE cells resulted in mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased expression of fission proteins-phospho-DRP1, increased mitochondrial ROS (mtROS), and decreased levels of ATP. BRPM2.5 altered the mitochondrial metabolism of 16HBE cells by decreasing mitochondrial oxygen consumption and glycolysis. However, Mitochondria targeted peptide SS-31 eliminated mitochondrial ROS and alleviated the ATP deficiency and proinflammatory cytokines release. BRPM2.5 exposure resulted in abnormal mitochondrial morphological alterations both in 16HBE and in lung tissue. Taken together, these results suggest that BRPM2.5 has detrimental effects on human airway epithelial cells, leading to mitochondrial dysfunction, abnormal mitochondrial metabolism and altered mitochondrial dynamics. The present study provides the first evidence that disruption of mitochondrial structure and mitochondrial metabolism may be one of the mechanisms of BRPM2.5-induced respiratory dysfunction.

Changes in the gut microbiome and metabolome in a rat model of pulmonary arterial hypertension.

The gut microbiota is widely considered to be involved in several diseases, including atherosclerosis, obesity, chronic obstructive pulmonary disease (COPD) and pulmonary arterial hypertension (PAH). This study aimed to determine if changes in the gut microbiome and metabolome play a major role in the early pathogenesis of PAH. Male Wistar rats were injected with monocrotaline (MCT) (55 mg/kg) at day 1 and injected with calcium-sensing receptor (CaSR) antagonist NPS2143 (4.5 mg/kg/d) from days 1 to 21. Fecal samples were obtained. The gut microbiota and metabolome were analyzed by 16S rRNA gene sequencing and mass spectrometry-based analysis to investigate the effect of PAH in this rat model. MCT injection had a marked effect on the composition of the gut microbiota. This finding was further confirmed by metabolomic analysis with identification of several metabolites relevant to the gut microflora. However, NPS2143 partially abrogated this intestinal flora disorder and reversed fecal metabolite abnormalities. In conclusion, our study shows correlations between changes in the gut microbiome and the metabolome in PAH, which are affected by NPS2143.

A novel function of calcium sensing receptor in chronic hypoxia-induced pulmonary venous smooth muscle cells proliferation.

Chronic hypoxia (CH) causes remodeling not only in pulmonary arteries but also in pulmonary veins. Pulmonary vascular remodeling stems from increased pulmonary vascular myocyte proliferation. However, the pathogenesis of CH-induced proliferation of pulmonary venous smooth muscle cells (PVSMCs) remains unknown. The present study aimed to explore the mechanisms by which CH affects PVSMCs proliferation. PVSMCs were isolated from rat distal pulmonary veins and exposed to CH (4% O2 for 60 h). The expression of calcium sensing receptor (CaSR) was determined by immunofluorescence, real-time quantitative PCR and Western blotting. Cell proliferation was assessed by cell counting, CCK-8 assay, and BrdU incorporation. Apoptosis analysis was examined by flow cytometry. In rat distal PVSMCs, CH increased the cell number and cell viability and enhanced DNA synthesis, which is accompanied by upregulated mRNA and protein expression levels of CaSR. Two negative CaSR modulators (NPS2143, NPS2390) not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs, whereas two positive modulators (spermine, R568) not only amplified CH-induced CaSR upregulation but also intensified CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs. Silencing CaSR with siRNA similarly attenuated the CH-induced enhancement of cell number, cell viability and DNA synthesis in PVSMCs. Neither CH nor downregulation of CaSR with siRNA had an effect on apoptosis in PVSMCs. These results suggest that CaSR mediating excessive proliferation is a new pathogenic mechanism involved in the initiation and progression of distal PVSMCs proliferation under CH conditions.