Mitochondria regulate not only cell functions through energy generation but also aging-associated cell phenotypes. Impaired mitochondrial structural and functional integrity accompanied by excessive ...mitochondrial reactive oxygen species (mtROS) production is associated with enhanced programmed cell death (PCD) and cellular senescence. Dysregulation of mechanisms for mitochondrial integrity, including mitophagy, induces accumulation of mitochondrial damage. Mitophagy is a highly conserved mechanism of selectively delivering damaged mitochondria for lysosomal degradation and is mainly governed by phosphatase and tensin homolog (PTEN)-induced putative protein kinase 1 (PINK1) and PARK2. Accumulating evidence suggests that PINK1-PARK2-mediated mitophagy has an important role in the pathogenesis of aging-associated pulmonary disorders, represented by chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). COPD characterized by progressive airflow limitation is mainly caused by cigarette smoke (CS) exposure, and accumulation of damaged mitochondria in bronchial epithelial cells (BEC) has been demonstrated. Intriguingly, both enhanced and impaired mitophagy have been implicated in COPD pathogenesis. Enhanced mitophagy induced by increased PINK1 expression has been associated with programmed necrosis, necroptosis. On the other hand, reduced PARK2 levels were linked to insufficient mitophagy, resulting in accelerated cellular senescence in BEC. Although dominant involvement of PCD and cellular senescence remains unclear, PINK1-PARK2-mediated mitophagy regulates mitochondrial ROS and cell fate during COPD pathogenesis. Involvement of insufficient mitophagy has been proposed in lung fibrosis development during IPF pathogenesis. Accumulation of dysmorphic mitochondria and increased ROS production linked to decrease in PINK1 expression were demonstrated in type II alveolar epithelial cells (AECIIs) in IPF lungs, which can be associated with enhanced apoptosis and cellular senescence. Furthermore, reduced PARK2 expression levels have been shown in myofibroblasts in IPF lungs. Insufficient mitophagy caused by PARK2 deficiency induced mtROS production with concomitantly activated platelet-derived growth factor receptor (PDGFR)/mammalian target of rapamycin (mTOR) signaling, resulting in increased myofibroblast differentiation and proliferation. Inappropriate PINK1-PARK2-mediated mitophagy appears to be mainly responsible for regulating cell fate, including PCD, cellular senescence, and myofibroblast differentiation during COPD and IPF pathogeneses. Modalities to achieve specific and appropriate levels of PINK1-PARK2-mediated mitophagy activation may be a promising therapeutic option to regulate the aging-associated pathology, COPD, and IPF.
Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in ...excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.
It is currently thought that extracellular vesicles (EVs), such as exosomes and microvesicles, play an important autocrine/paracrine role in intercellular communication. EVs package proteins, mRNA ...and microRNA (miRNA), which have the ability to transfer biological information to recipient cells in the lungs. Depending on their origin, EVs fulfil different functions. EVs derived from mesenchymal stem cells (MSCs) have been found to promote therapeutic activities that are comparable to MSCs themselves. Recent animal model-based studies suggest that MSC-derived EVs have significant potential as a novel alternative to whole-cell therapies. Compared to their parent cells, EVs may have a superior safety profile and can be stored without losing function. It has been observed that MSC-derived EVs suppress pro-inflammatory processes and reduce oxidative stress, pulmonary fibrosis and remodeling in a variety of in vivo inflammatory lung disease models by transferring their components. However, there remain significant challenges to translate this therapy to the clinic. From this view point, we will summarize recent studies on EVs produced by MSCs in preclinical experimental models of inflammatory lung diseases. We will also discuss the most relevant issues in bringing MSC-derived EV-based therapeutics to the clinic for the treatment of inflammatory lung diseases.
To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, ...releasing damage-associated molecular patterns and driving tissue inflammation. Necroptosis is a well-understood form of regulated necrosis that is executed by RIPK3 (receptor-interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase domain-like protein). Ferroptosis is a newly described caspase-independent form of regulated necrosis that is characterized by the increase of detrimental lipid reactive oxygen species produced via iron-dependent lipid peroxidation. The role of these two cell death pathways differs depending on the disease, cell type, and microenvironment. Moreover, some experimental cell death models have demonstrated shared ferroptotic and necroptotic cell death and the synergistic effect of simultaneous inhibition. This review examines the role of regulated necrotic cell death, particularly necroptosis and ferroptosis, in lung disease pathogenesis in the context of recent insights into the roles of the key effector molecules of these two cell death pathways.
Semi-quantitative CT score is generally used for evaluating the disease status of Mycobacterium abscessus (Mab) Pulmonary disease (Mab-PD). However, its accuracy and clinical usefulness are limited, ...since the CT score is largely affected by coexisting lung disease. Hence, we hypothesized that numerical change in CT score during the observation period may be useful for evaluating disease activity of Mab-PD.
Patients diagnosed with Mab-PD based on the official ATS/ERS/ESCMID/IDSA statement at Jikei University Hospital and Jikei Daisan Hospital between 2015 January 1 and 2021 July 31 were included (n = 32). We reviewed the medical records, and bacteriological and laboratory data of the patients. Chest CT was performed at diagnosis in all 32 cases. In 18 cases, chest CT images within 4 years before diagnosis were available. The numerical change in CT score between two time points was calculated and the association of the CT scores with sputum Gaffky score and serum CRP was examined.
CT score at diagnosis was not correlated with sputum Gaffky score nor serum CRP, while the difference of absolute value and change rate in CT score between at diagnosis and immediate past CT were well correlated with both sputum Gaffky score and serum CRP.
Chronological change in CT score may more precisely reflect the disease activity of airway mycobacterial burden and systemic inflammation in Mab-PD at the timing of diagnosis.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Aging is associated with impairments in homeostasis. Although aging and senescence are not equivalent, the number of senescent cells increases with aging. Cellular senescence plays important ...roles in tissue repair or remodeling, as well as embryonic development. Autophagy is a process of lysosomal self-degradation that maintains a homeostatic balance between the synthesis, degradation, and recycling of cellular proteins. Autophagy diminishes with aging; additionally, accelerated aging can be attributed to reduced autophagy. Cellular senescence has been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease of accelerated lung aging, presumably by impairing cell repopulation and by aberrant cytokine secretion in the senescence-associated secretory phenotype. The possible participation of autophagy in the pathogenic sequence of COPD has been extensively explored. Although it has been reported that increased autophagy may induce epithelial cell death, an insufficient reserve of autophagy can induce cellular senescence in bronchial epithelial cells of COPD. Furthermore, advanced age is one of the most important risk factors for the development of idiopathic pulmonary fibrosis (IPF). Telomere shortening is found in blood leukocytes and alveolar epithelial cells from patients with IPF. Accelerated senescence of epithelial cells plays a role in IPF pathogenesis by perpetuating abnormal epithelial-mesenchymal interactions. Insufficient autophagy may be an underlying mechanism of accelerated epithelial cell senescence and myofibroblast differentiation in IPF. Herein, we review the molecular mechanisms of cellular senescence and autophagy and summarize the role of cellular senescence and autophagy in both COPD and IPF.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
Lysosome‐associated membrane protein type 2a (LAMP2A) is the key receptor protein of chaperone‐mediated autophagy (CMA). Downregulation of LAMP2A leads to CMA blockade. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes through CMA modulation and represents a promising new target against chemoresistant non–small cell lung cancer (NSCLC).
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mitochondria play important roles in the maintenance of intracellular homeostasis; hence, the quality control of mitochondria is crucial for cell fate determination. Mitochondria dynamics and ...mitochondria-specific autophagy, known as mitophagy, are two main quality control systems in cells. Mitochondria fuse to increase energy production in response to stress, and damaged mitochondria are segregated by fission and degraded by mitophagy. Once these systems are disrupted, dysfunctional mitochondria with decreased adenosine triphosphate (ATP) production and increased reactive oxygen species (ROS) production accumulate, affecting cell fate. Recently, increasing evidence suggests that the dysregulation of mitochondria quality control is pathogenic in several age-related diseases. In this review, we outlined the role of mitochondria quality control systems in the pathogenesis of age-associated lung diseases, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent advances in aging research have provided novel insights for the development of senotherapy, which utilizes cellular senescence as a therapeutic target. Cellular senescence is involved in the ...pathogenesis of various chronic diseases, including metabolic and respiratory diseases. Senotherapy is a potential therapeutic strategy for aging-related pathologies. Senotherapy can be classified into senolytics (induce cell death in senescent cells) and senomorphics (ameliorate the adverse effects of senescent cells represented by the senescence-associated secretory phenotype). Although the precise mechanism has not been elucidated, various drugs against metabolic diseases may function as senotherapeutics, which has piqued the interest of the scientific community. Cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are aging-related respiratory diseases. Large-scale observational studies have reported that several drugs, such as metformin and statins, may ameliorate the progression of COPD and IPF. Recent studies have reported that drugs against metabolic diseases may exert a pharmacological effect on aging-related respiratory diseases that can be different from their original effect on metabolic diseases. However, high non-physiological concentrations are needed to determine the efficacy of these drugs under experimental conditions. Inhalation therapy may increase the local concentration of drugs in the lungs without exerting systemic adverse effects. Thus, the clinical application of drugs against metabolic diseases, especially through an inhalation treatment modality, can be a novel therapeutic approach for aging-related respiratory diseases. This review summarizes and discusses accumulating evidence on the mechanisms of aging, as well as on cellular senescence and senotherapeutics, including drugs against metabolic diseases. We propose a developmental strategy for a senotherapeutic approach for aging-related respiratory diseases with a special focus on COPD and IPF.
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.
PDF
