Inadequate autophagy promotes smoking-induced cellular senescence involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome axis. For the first time, we investigated the therapeutic potential of pemafibrate, a putative TFEB inducer. COPD lung epithelial cells showed reduced TFEB expression. Pemafibrate enhanced autophagy/mitophagy flux and restored lysosomal acidification observed during cigarette smoke (CS) extract exposure in human bronchial epithelial cells, resulting in reduced cellular senescence. TFEB knockdown demonstrated involvement of pemafibrate-induced TFEB in these effects. Pemafibrate induced TFEB expression, mitigated alveolar enlargement and airflow obstruction, and attenuated the CS-induced increase in static lung compliance in a long-term CS-exposed mouse model. It reduced the CS exposure-induced cellular senescence, possibly through autophagy/mitophagy, as suggested by bulk RNA sequencing of mouse lungs. A retrospective cohort study showed that patients given pemafibrate displayed attenuated FEV1.0 decline compared with those given bezafibrate or fenofibrate. In conclusion, pemafibrate is a promising therapeutic agent for COPD, potentially exerting its effects through the regulation of the TFEB-autophagy/mitophagy-lysosome axis. ### Competing Interest Statement JA is a recipient of support from a collaborative research fund from Kowa Company, Ltd. Kowa Company, Ltd. had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the abstract, or in the decision to present the results. Rest of the authors declare no conflict of interest. Pemafibrate was provided by Kowa Company, Ltd. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee of The Jikei University School of Medicine (Tokyo, Japan) gave ethical approval for the use of human lung tissues, including those used for human bronchial epithelial cell isolation, obtained from patients undergoing pneumonectomy or lobectomy for primary lung cancer [approval no. 20-153(5443)].Written informed consent was obtained from all participants who underwent surgery as part of this approved ongoing research protocol. The Ethics committee of The Jikei University School of Medicine (Tokyo, Japan) gave ethical approval for the retrospective cohort study [approval no. 34-171(113229). The requirement for informed consent was waived because of the retrospective study design, in accordance with the ethics guidelines of The Jikei University School of Medicine, and an opt-out notice was posted on the hospital website. All clinical data were anonymized to protect participant privacy. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availabitily Raw and processed RNA-seq data generated in this study are being deposited in the NCBI Gene Expression Omnibus. The accession number will be provided upon revision. the Project for the Ministry of Education, Culture, Sports, Science, and Technology KAKENHI Grant-in-Aid for Young Scientists, 21K16123 the Project for the Ministry of Education, Culture, Sports, Science, and Technology KAKENHI Grant-in-Aid for Scientific Research B, 22H03082 the Project for the Ministry of Education, Culture, Sports, Science, and Technology KAKENHI Grant-in-Aid for Scientific Research C, 21K08213 The Jikei University Strategic Prioritizing Research Fund, Research Fund 2024 Kowa Company, Ltd. (Tokyo, Japan), a research grant

Acute lung injury (ALI) is characterized by respiratory failure resulting from the disruption of the epithelial and endothelial barriers as well as immune system. In this study, we evaluated the therapeutic potential of airway epithelial cell-derived extracellular vesicles (EVs) in maintaining lung homeostasis. We isolated human bronchial epithelial cell-derived EVs (HBEC-EVs), which endogenously express various immune-related surface markers and investigated their immunomodulatory potential in ALI. In ALI cellular models, HBEC-EVs demonstrated immunosuppressive effects by reducing the secretion of proinflammatory cytokines in both THP-1 macrophages and HBECs. Mechanistically, these effects were partially ascribed to nine of the top 10 miRNAs enriched in HBEC-EVs, governing toll-like receptor-NF-κB signaling pathways. Proteomic analysis revealed the presence of proteins in HBEC-EVs involved in WNT and NF-κB signaling pathways, pivotal in inflammation regulation. ANXA1, a constituent of HBEC-EVs, interacts with formyl peptide receptor (FPR)2, eliciting anti-inflammatory responses by suppressing NF-κB signaling in inflamed epithelium, including type II alveolar epithelial cells. In a mouse model of ALI, intratracheal administration of HBEC-EVs reduced lung injury, inflammatory cell infiltration, and cytokine levels. Collectively, these findings suggest the therapeutic potential of HBEC-EVs, through their miRNAs and ANXA1 cargo, in mitigating lung injury and inflammation in ALI patients.

Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargomediated fibroblast-tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.

Background: Accelerated cellular senescence has been implicated in the pathogenesis of COPD and dysregulation of autophagy-lysosome axis may play a pivotal role in regulating smoking-induced cellular senescence. Transcription factor EB (TFEB) is a master regulator of autophagy-lysosome axis and TFEB malfunction has been demonstrated in COPD lungs. Recent advances suggest that senotherapy targeting cellular senescence is a promising approach for aging-related pathology. Aims and objectives: To elucidate the senotherapeutic potential of pemafibrate, a putative inducer of TFEB, through activating autophagy-lysosome axis. Methods: TFEB expression levels in COPD samples were evaluated. The regulatory role of pemafibrate-mediated TFEB expression was examined in cigarette-smoke extract (CSE)-induced autophagy/mitophagy activation, lysosomal dysfunction, and cellular senescence in human bronchial epithelial cells (HBEC) and cigarette-smoke (CS)-exposure mouse models. Results: TFEB expression levels were reduced in epithelial cells in COPD lungs. Pemafibrate enhanced autophagy/mitophagy flux and restored lysosomal acidification, resulting in reduced cellular senescence during CSE exposure in HBEC. Involvement of pemafibrate-induced TFEB was elucidated by means of TFEB knockdown experiments. Pemafibrate induced TFEB expression and mitigated alveolar enlargement, airflow obstruction, and increased static lung compliance in long term CS exposure mouse model. CS exposure-induced cellular senescence was reduced and the analysis using RNA-seq data from mouse lungs elucidated the involvement of mitophagy. Conclusions: Pemafibrate may exert senotherapeutic property against COPD pathogenesis via regulating TFEB-mitophagy axis.

We herein report two cases of cerebrospinal fluid (CSF) rhinorrhea associated with lung infiltrates. One patient presented with symptomatic non-resolving pneumonia, while the other was asymptomatic. In both cases, the lung infiltrates completely resolved when CSF leakage had subsided. Pulmonary involvement in CSF rhinorrhea is under-recognized, and despite being the definitive treatment, surgery for CSF rhinorrhea is typically postponed due to the presence of lung infiltrates. However, meningitis is a serious complication due to a delay in surgical management. Physicians should be made aware that CSF rhinorrhea is a potential cause of intractable lung infiltrates.

Abstract Background Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin‐mediated mitophagy, a mitochondrion‐selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD‐related sarcopenia. Methods The involvement of Parkin‐mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS‐exposure model using Parkin−/− mice, and human muscle samples from patients with COPD‐related sarcopenia. Results Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin‐mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF‐1)‐mediated myosin heavy chain (MHC) degradation. Parkin−/− mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF‐1 expression (P < 0.01) compared with wild‐type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD‐related sarcopenia exhibited significantly reduced Parkin but increased MuRF‐1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation‐induced muscle contraction prevented CSE‐induced MHC reduction by maintaining Parkin levels in myotubes. Conclusions Taken together, COPD‐related sarcopenia can be attributed to insufficient Parkin‐mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF‐1 activation, which may be at least partly preventable through optimal physical exercise.

Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

BACKGROUND:Anti-aquaporin-4 (AQP4) antibody is an autoantibody marker often observed in patients with neuromyelitis optica spectrum disorder (NMOSD). The pathological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD remains unclear. We aimed to assess the clinical and histological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD.METHODS:We retrospectively reviewed the medical records of 52 patients with anti-AQP4 antibody-positive NMOSD and conducted immunohistochemical evaluations of the lung biopsy specimens.RESULTS:Among 52 patients with anti-AQP4 antibody-positive NMOSD, 4 patients showed pulmonary involvement with a diagnosis of organizing pneumonia (OP). The proportion of males was larger (75% vs. 12.5%; p = 0.013) and creatine kinase levels were higher (458.3 U/L vs. 83.9 U/L; p = 0.003) in patients with OP than in those without OP. OP development preceded or coincided with the NMOSD symptoms. Chest computed tomography findings were consistent with OP in all four patients. Bronchoalveolar lavage fluid predominantly contained lymphocytes. Transbronchial lung biopsy revealed intraluminal plugs of inflammatory debris within the alveoli. Alveolar epithelial cells covering the OP lesions exhibited AQP4 loss, immunoglobulin G deposition, and complement activation. Corticosteroid treatment resulted in clinical improvement of OP.CONCLUSION:OP may be considered a pulmonary manifestation of anti-AQP4 antibody-positive NMOSD beyond the central nervous system. Complement-dependent cytotoxicity of the lung epithelial cells caused by anti-AQP4 antibody is at least partly involved in OP development. When diagnosing NMOSD, the possibility of OP should be carefully evaluated based on the detailed history and chest imaging findings.

The unperturbed lung is highly quiescent, with a remarkably low level of cell turnover. However, once damaged, the lung shows an extensive regenerative capacity, with resident progenitor cell populations re-entering the cell cycle and differentiating to promote repair. This quick and dramatic repair response requires interactions among more than 40 different cell lineages in the lung, and defects in any of these processes can lead to various lung pathologies. Understanding the mechanisms of interaction in lung injury, repair and regeneration thus has considerable practical and therapeutic implications. Moreover, therapeutic strategies for replacing lung progenitor cells and their progeny through cell therapy have gained increasing attention. In the last decade, extracellular vesicles (EVs), including exosomes, have been recognised as paracrine mediators through the transfer of biological cargo. Recent work has revealed that EVs are involved in lung homeostasis and diseases. In addition, EVs derived from specific cells or tissues have proven to be a promising cell-free modality for the treatment of lung diseases. This review highlights the EV-mediated cellular crosstalk that regulates lung homeostasis and discusses the potential of EV therapeutics for lung regenerative medicine.

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Results: A total of 1016 patients (524 with IIPs, including 145 CPFE, and 491 with COPD) were enrolled.96.8% of COPD patients and 69.9% of IIPs patients were current or former smokers.The telomerase reverse transcriptase (TERT) rs2736100 was associated with the risk of IPF and COPD.Conclusion: This study revealed the current status of lung diseases potentially related to tobacco smoking in Fukuoka Prefecture.In addition, some results of study on genetic factors will be reported.

were higher. Although the COPD state is proposed to be related to F. nucleatum, the mechanism is unclear. In this study, we investigated the effect of F. nucleatum aspiration on COPD exacerbation at the molecular level. Methods: By using an elastase-induced emphysema mouse model mimicking COPD, we explored the effect of intratracheally administered heat-killing F. nucleatum on cellular and molecular responses in the lung and subsequent disease progression. Result and Conclusions: In mice with elastase-induced emphysema, F. nucleatum administration resulted in increased: mean linear intercept, number of inflammatory cells in bronchoalveolar lavage fluid, both inflammatory cytokine expression and MUC5AC production in the lungs, as well as enhanced emphysema progression. Taken together, these results suggest that F. nucleatum aspiration exacerbates elastase-induced emphysema. In this regard, we propose that periodontal disease could elevate the risk of severe COPD.

Abstract Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF.

Background: COPD has been found to be caused by impairment of lung development.Preserved ratio impaired spirometry (PRISm) is thought to be a subtype of lung growth impairment and is associated with COPD.We hypothesized that the association between PRISm and COPD has sexspecific differences.To prove this, we examined the association by using the medical check-up data.Methods: This retrospective study included medical checkup subjects who visited the Kochi Medical check-up Clinic for medical check-up at both period 1 (2014-2016) and 2 (2017-2019).The mean duration from P1 to P2 was 1042 AE 323 days.COPD was defined as a FEV1/FVC ratio < lower limit of normal (LLN) without bronchodilators in this study.PRISm was defined as a FEV1/FVC ratio > LLN and percent FEV1 (FEV1/predicted FEV1) < 80%.Results: Of 1672 subjects (mean age AE SD: 56.5AE9.5),976 (58.4%) were male.The prevalence of PRISm was 10.5% in period 1 and 8.9% in period 2. The percentage of subjects who progressed to COPD was higher in PRISm than in normal lung function group (odds ratio:2.62,p=0.014).In logistic regression analysis, PRISm was an independent risk factor for developing COPD (odds ratio:3.75,p<0.01).It analyzed for sex-specific differences, PRISm was a risk factor for developing COPD in male (p<0.05),but not in female (p = 0.787).

Background and Aims: Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts.The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so atypical HRCT appearances present challenges to establishing the proper LAM diagnosis.The objective of this study is to accrue atypical chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients.Methods: We retrospectively evaluated radiologic findings of chest HRCT (with a section thickness of 2 mm) from 311 females, including 272 patients with S-LAM (mean age 39.2 years) and 39 patients with TSC-LAM (mean age 38.3 years) who were seen at our hospital between April 2009 and December 2016.Results: We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and atypical findings in addition to cysts.We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction.The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules.

Respiratory diseases and their comorbidities, such as cardiovascular disease and muscle atrophy, have been increasing in the world. Extracellular vesicles (EVs), which include exosomes and microvesicles, are released from almost all cell types and play crucial roles in intercellular communication, both in the regulation of homeostasis and the pathogenesis of various diseases. Exosomes are of endosomal origin and range in size from 50 to 150 nm in diameter, while microvesicles are generated by the direct outward budding of the plasma membrane in size ranges of 100–2,000 nm in diameter. EVs can contain various proteins, metabolites, and nucleic acids, such as mRNA, non-coding RNA species, and DNA fragments. In addition, these nucleic acids in EVs can be functional in recipient cells through EV cargo. The endothelium is a distributed organ of considerable biological importance, and disrupted endothelial function is involved in the pathogenesis of respiratory diseases such as chronic obstructive pulmonary disease, pulmonary hypertension, and acute respiratory distress syndrome. Endothelial cell-derived EVs (EC-EVs) play crucial roles in both physiological and pathological conditions by traveling to distant sites through systemic circulation. This review summarizes the pathological roles of vascular microRNAs contained in EC-EVs in respiratory diseases, mainly focusing on chronic obstructive pulmonary disease, pulmonary hypertension, and acute respiratory distress syndrome. Furthermore, this review discusses the potential clinical usefulness of EC-EVs as therapeutic agents in respiratory diseases.

Abstract The clinical manifestations of COVID‐19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID‐19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID‐19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID‐19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID‐19 severity. Strikingly, we identified three distinct groups of markers (antiviral response‐related EV proteins, coagulation‐related markers, and liver damage‐related exRNAs) with the potential to serve as early predictive biomarkers for COVID‐19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID‐19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00‐1.00)). The validation set included 40 COVID‐19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73‐0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID‐19 therapy.

Fibrosis is commonly characterized by the extensive accumulation of extracellular matrix components during wound healing in response to tissue injury, and can lead to distortion of tissue architecture and loss of organ function. Fibrogenesis is a highly orchestrated process determined by defined sequences of molecular signals and cellular response mechanisms. Understanding the molecular mechanisms have advanced the prospect of developing therapies for disease regression. Recently, extracellular vesicles (EVs) have attracted considerable attention in fibrosis research. In this chapter, we summarize the current knowledge of the involvement of EVs in fibrotic diseases including liver, lung and heart. We also propose EV-based biomarkers and treatments in fibrotic diseases.

Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome-associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non-small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC-bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.