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Bronchial and pleural injuries with persistent air leak pose a threat in the repair and regeneration of pulmonary diseases. The need to arrive at a highly efficient therapy for closure of bronchopleural fistula (BPF) so as to effectively suppress inflammation, infection and repair the damaged pleural space caused by cancer as well as contractile restoration of bronchopleural scars remain a significant clinical challenge. Herein, we have designed and developed potent bioactive vitamin K3 carnosine peptide (VKC)-loaded spun SF fibroin fibers/collagen bi-layered 3D scaffold for bronchopleural fistula tissue engineering applications. The VKC drug showed excellent cell viability in human bronchial epithelial cells (HBECs), in addition to its pronounced higher cytotoxicity against the A549 lung cancer cell line with an IC 50 of 5 μg/mL. Furthermore, VKC displayed a strong affinity with the catalytic site of EGFR (PDB ID: 1M17) and VEGFR2 (PDB ID: 4AGD, 4ASD) receptors in molecular docking studies. Following which the spun SF-VKC (primary layer) and collagen film (top layer) constructed bi-layered CSVKC were structurally elucidated and its morphological, physicochemical and biological characterizations were well examined. The bi-layered scaffold showed superior biocompatibility and cell migration ability in HBECs than other scaffolds. Interestingly, the CSVKC revealed rapid HBECs motility towards scratched regions for fast healing in vitro bronchial tissue engineering. In vivo biocompatibility and angiogenesis studies of the prepared scaffolds were evaluated and the results obtained demonstrated excellent new tissue formation and neovascularization in the bi-layered architecture rather than others. Therefore, our results suggest that the potent antibacterial and anticancer therapeutic agent (VKC)-impregnated silk fibroin fibers/collagen bi-layered 3D biomaterial could be useful in treating cancerous BPF and pulmonary diseases in future., (Copyright © 2022. Published by Elsevier B.V.)

This chapter overviews roles of DNA methylation in inflammatory cell biology with the focuses on lymphocytes and macrophages/monocytes in lung diseases, although the molecular mechanisms by which target genes are methylated and regulated in lung diseases remain unclear. Most of epigenetic studies on DNA methylation of target genes in lung diseases mainly demonstrated the correlation of DNA methylation of target genes with the levels of other corresponding factors, with the specificity of clinical phenomes, and with the severity of lung diseases. There is an urgent need to identify and validate the specificity and regulatory mechanisms of inflammatory cell epigenetics in depth. The epigenetic heterogeneity among different subsets of T cells and among promoters or non-promoters of target genes should be furthermore clarified in acute or chronic lung diseases and cancers. The hyper/hypo-methylation and modifications of chromosol and extrachromosomal DNA may result in alternations in proteins within inflammatory cells, which can be identified as disease-specific biomarkers and therapeutic targets.

Single cell sequencing is important to detect the gene heterogeneity between cells, as the part of single-cell systems biology which combines computational science, mathematical modelling and high-throughput technologies with biological function and organization in the cell. We initially arise the question how to integrate the outcomes of single-cell systems biology with clinical phenotype, interpret alterations of single-cell gene sequencing and function in patient response to therapies, and understand the significance of single-cell systems biology in the discovery and development of new molecular diagnostics and therapeutics. The present review furthermore focuses the significance of singe cell systems biology in respiratory diseases and calls the special attention from scientists who are working on single cell systems biology to improve the diagnosis and therapy for patients with lung diseases.

This study explores the role and potential mechanisms of microRNA-125b-5p (miR-125b-5p) in pulmonary fibrosis (PF). PF is a typical outcome of many chronic lung diseases, with poor prognosis and the lack of appropriate medical treatment because PF's molecular mechanisms remain poorly understood. In this study, using in vitro and in vivo analyses, we find that miR-125b-5p is likely a potent regulator of lung fibrosis. The findings reveal that, on the one hand, miR-125b-5p not only specifically decreases in the epithelial-mesenchymal transition (EMT) of lung epithelial cells, but also shows a downregulation trend in the lung tissues of mice with PF. On the other hand, overexpression of miR-125b-5p on the cellular and animal levels downregulates EMT and fibrotic phenotypes, respectively. To clarify the molecular mechanism of the "therapeutic" effect of miR-125b-5p, we use the target prediction tool combined with a dual luciferase assay and complete a rescue experiment by constructing the overexpression vector of the target gene Bcl-2 homologous antagonist/ killer (BAK1), thus confirming that miR-125b-5p can effectively inhibit EMT and fibrosis process by targeting BAK1 gene. MiR-125b-5p inhibits the EMT in lung epithelial cells by negatively regulating BAK1, while overexpression of miR-125b-5p can alleviate lung fibrosis. The findings suggest that MiR-125b-5p/BAK1 can serve as a potential treatment target for PF. [ABSTRACT FROM AUTHOR]

Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking‐induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell‐lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism‐associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2‐mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases. [ABSTRACT FROM AUTHOR]

Gasdermin (GSDM) family, the key executioners of pyroptosis, play crucial roles in anti-pathogen and anti-tumor immunities, although little is known about the expression of GSDM in lung diseases at single-cell resolution, especially in lung epithelial cells. We comprehensively investigated the transcriptomic profiles of GSDM members in various lung tissues from healthy subjects or patients with different lung diseases at single cell level, e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), lung adenocarcinoma (LUAD), or systemic sclerosis (SSC). The expression of GSDM members varied among pulmonary cell types (immune cells, structural cells, and especially epithelial cells) and even across lung diseases. Regarding disease-associated specificities, we found that GSDMC or GSDMD altered significantly in ciliated epithelia of COPD or LUAD, GSDMD in mucous, club, and basal cells of LUAD and GSDMC in mucous epithelia of para-tumor tissue, as compared with the corresponding epithelia of other diseases. The phenomic specificity of GSDM in lung cancer subtypes was noticed by comparing with 15 non-pulmonary cancers and para-cancer samples. GSDM family gene expression changes were also observed in different lung epithelial cell lines (e.g., HBE, A549, H1299, SPC-1, or H460) in responses to external challenges, including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and AR2 inhibitor at various doses or durations. GSDMA is rarely expressed in those cell lines, while GSDMB and GSDMC are significantly upregulated in human lung epithelia. Our data indicated that the heterogeneity of GSDM member expression exists at different cells, pathologic conditions, challenges, probably dependent upon cell biological phenomes, functions, and behaviors, upon cellular responses to external changes, and the nature and severity of lung disease. Thus, the deep exploration of GSDM phenomes may provide new insights into understanding the single-cell roles in the tissue, regulatory roles of the GSDM family in the pathogenesis, and potential values of biomarker identification and development. [ABSTRACT FROM AUTHOR]

Chronic lung diseases represent a largely global burden whose pathogenesis remains largely unknown. Research increasingly suggests that epigenetic modifications, especially DNA methylation, play a mechanistic role in chronic lung diseases. DNA methylation can affect gene expression and induce various diseases. Of the caveolae in plasma membrane of cell, caveolin‐1 (Cav‐1) is a crucial structural constituent involved in many important life activities. With the increasingly advanced progress of genome‐wide methylation sequencing technologies, the important impact of Cav‐1 DNA methylation has been discovered. The present review overviews the biological characters, functions, and structure of Cav‐1; epigenetic modifications of Cav‐1 in health and disease; expression and regulation of Cav‐1 DNA methylation in the respiratory system and its significance; as well as clinical potential as disease‐specific biomarker and targets for early diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: The morbidity and mortality of patients with critical illnesses remain high in pulmonary critical care units and a poorly understood correlation between alterations of lipid elements and clinical phenomes remain unelucidated.Methods: In the present study, we investigated plasma lipidomic profiles of 30 patients with severe acute pneumonia (SAP), acute pulmonary embolism (APE), and acute exacerbation of chronic pulmonary diseases (AECOPD) or 15 healthy with the aim to compare disease specificity of lipidomic patterns. We defined the specificity of lipidomic profiles in SAP by comparing it to both APE and AECOPD. Analysis of the correlation between altered lipid elements and clinical phenotypes using the lipid-QTL model was then carried out.Results: We integrated lipidomic profiles with clinical phenomes measured by score values from the digital evaluation score system and found phenome-associated lipid elements to identify disease-specific lipidomic profiling. The present study demonstrates that lipidomic profiles of patients with acute lung diseases are different from healthy lungs, and there are also disease-specific portions of lipidomics among SAP, APE, or AECOPD. The comprehensive profiles of clinical phenomes or lipidomics are valuable in describing the disease specificity of patient phenomes and lipid elements. The combination of clinical phenomes with lipidomic profiles provides more detailed disease-specific information on panels of lipid elements When compared to the use of each separately.Conclusions: Integrating biological functions with disease specificity, we believe that clinical lipidomics may create a new alternative way to understand lipid-associated mechanisms of critical illnesses and develop a new category of disease-specific biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]