Novel Populations of Lung Capillary Endothelial Cells and Their Functional Significance.

The role of the lung's microcirculation and capillary endothelial cells in normal physiology and the pathobiology of pulmonary diseases is unequivocally vital. The recent discovery of molecularly distinct aerocytes and general capillary (gCaps) endothelial cells by single-cell transcriptomics (scRNAseq) advanced the field in understanding microcirculatory milieu and cellular communications. However, increasing evidence from different groups indicated the possibility of more heterogenic structures of lung capillaries. Therefore, we investigated enriched lung endothelial cells by scRNAseq and identified five novel populations of gCaps with distinct molecular signatures and roles. Our analysis suggests that two populations of gCaps that express Scn7a(Na+) and Clic4(Cl-) ion transporters form the arterial-to-vein zonation and establish the capillary barrier. We also discovered and named mitotically-active "root" cells (Flot1+) on the interface between arterial, Scn7a+, and Clic4 + endothelium, responsible for the regeneration and repair of the adjacent endothelial populations. Furthermore, the transition of gCaps to a vein requires a venous-capillary endothelium expressing Lingo2. Finally, gCaps detached from the zonation represent a high level of Fabp4, other metabolically active genes, and tip-cell markers showing angiogenesis-regulating capacity. The discovery of these populations will translate into a better understanding of the involvement of capillary phenotypes and their communications in lung disease pathogenesis.

Cystic Fibrosis Transmembrane Conductance Regulator Protein Modulators in Children and Adolescents with different CF Genotypes - Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the efficacy of the first triple CFTR protein modulators in children and adolescents with cystic fibrosis. METHODS: Systematic review and meta-analysis were conducted, following PRISMA guidelines. The following databases were searched extensively: PubMed/Medline, Clinical trials.gov, Google Scholar, Scopus, Embase, and Europe PMC using the keywords: "Ivacaftor," "Elexacaftor," "Tezacaftor," VX_661", VX_770", "VX_445", "cystic fibrosis". A total of ten randomized clinical trials were included in our analysis. Primary outcomes included: Absolute change in predicted FEV1 from baseline, Absolute change in sweat chloride test from baseline, Absolute change in BMI from baseline, Absolute change in CF-QR from baseline, and Adverse Events. RESULTS: Among primary findings, significant absolute change in predictive FEV1 from baseline through 4 weeks favoured the triple CFTR protein modulators. [MD=11.80,95%CI=8.47_15.12, p value=<0.00001]; as well as CF_QR score [MD=0.00,95%CI=-2.50_2.50, p value=1.00], and BMI kg/m² change [MD=16.90,95%CI=12.73_21.06, p value=<0.00001]. No significant change was noted for CFTR channels activity in the treatment group when compared to placebo or VX_770/VX_661 [MD= -12.57,95%CI=-94.46_69.32, p value=0.76]. CONCLUSION: In children aged ≥ 6 y old and adolescents with F508del_CFTR mutation, Elexacaftor-Tezacaftor-Ivacaftor tend to be more effective than first-generation therapy, demonstrating promising results by exhibiting significant improvement in lung function, body weight, and respiratory-related quality of life.