Short-term PM2.5 exposure induces transient lung injury and repair.

Exposure to fine atmospheric particulate matter (PM) is known to induce lung inflammation and injury; however, the way in which sophisticated endogenous lung repair and regenerative programs respond to this exposure remains unknown. In this study, we established a whole-body mouse exposure model to mimic real scenarios. Exposure to fine PM (PM with an aerodynamic diameter ≤ 2.5 µm [PM2.5]; mean 1.05 mg/m3) for 1-month elicited inflammatory infiltration and epithelial alterations in the lung, which were resolved 6 months after cessation of exposure. Immune cells that responded to PM2.5 exposure mainly included macrophages and neutrophils. During PM2.5 exposure, alveolar epithelial type 2 cells initiated rapid repair of alveolar epithelial mucosa through proliferation. However, the reparative capacity of airway progenitor cells (club cells) was impaired, which may have been related to the oxidative production of neutrophils or macrophages, as suggested in organoid co-cultures. These data suggested that the pulmonary toxic effects of short-term exposure to fine atmospheric PM at a certain dosage could be overcome through tissue reparative mechanisms.

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19.

Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8+ T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future.

LKB1 deficiency upregulates RELM-α to drive airway goblet cell metaplasia.

Targeting airway goblet cell metaplasia is a novel strategy that can potentially reduce the chronic obstructive pulmonary disease (COPD) symptoms. Tumor suppressor liver kinase B1 (LKB1) is an important regulator of the proliferation and differentiation of stem/progenitor cells. In this study, we report that LKB1 expression was downregulated in the lungs of patients with COPD and in those of cigarette smoke-exposed mice. Nkx2.1Cre; Lkb1f/f mice with conditional loss of Lkb1 in mouse lung epithelium displayed airway mucus hypersecretion and pulmonary macrophage infiltration. Single-cell transcriptomic analysis of the lung tissues from Nkx2.1Cre; Lkb1f/f mice further revealed that airway goblet cell differentiation was altered in the absence of LKB1. An organoid culture study demonstrated that Lkb1 deficiency in mouse airway (club) progenitor cells promoted the expression of FIZZ1/RELM-α, which drove airway goblet cell differentiation and pulmonary macrophage recruitment. Additionally, monocyte-derived macrophages in the lungs of Nkx2.1Cre; Lkb1f/f mice exhibited an alternatively activated M2 phenotype, while expressing RELM-α, which subsequently aggravated airway goblet cell metaplasia. Our findings suggest that the LKB1-mediated crosstalk between airway progenitor cells and macrophages regulates airway goblet cell metaplasia. Moreover, our data suggest that LKB1 agonists might serve as a potential therapeutic option to treat respiratory disorders associated with goblet cell metaplasia.

Associations between CCL21 gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis.

Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by the development through angiogenesis, which is dependent on endothelial cell activation, migration and proliferation and CCL21 plays an important role in this pathology. Currently, CCL21 gene polymorphism studies on rheumatoid arthritis are scarce and the results are diverse. This meta-analysis was performed to determine if CCL21 gene polymorphisms correlate with the risk of developing RA. Association reports for the relationship between CCL21 polymorphisms and RA were identified from PubMed, Cochrane Library, Embase, SCIELO, CNKI and Wanfang databases on March 22, 2017. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias was conducted with Begg's funnel plot and Egger's regression test to measure the robustness of our findings. Sensitivity and cumulative analyses were used to assess the overall robustness of the study's results. Four relevant case-control cohort studies and three GWAS studies with CCL21rs2812378G>A gene polymorphisms and rheumatoid arthritis involving 9963 RA cases and 7976 controls were identified. Significant associations between the CCL21 rs2812378G>A polymorphism and RA risk were observed in the co-dominant model, dominant model and heterozygous model (A vs G: OR = 1.08, 95% CI = 1.03-1.14, p < 0.01, I 2 = 0.0%; AA + AG vs GG: OR = 1.15, 95% CI = 1.05-1.28, p < 0.01, I 2 = 0.0%; AG vs GG: OR = 1.18, 95% CI = 1.08-1.30, p < 0.01, I 2 = 3.8%) in the total population, as well as in subgroup Caucasian population. The combined analysis revealed a significantly increased risk of rheumatoid arthritis in the co-dominant model, dominant model and heterozygous model in overall population and subgroup Caucasian population.