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Nonislet tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome characterized by refractory hypoglycemia, which often requires multifaceted therapy. We reported a case of a patient with pleural malignant mesothelioma and developed NICTH, for which chemotherapy, glucocorticoids, and nutrition were given to achieve optimal glycemic control., In patients with tumors and hypoglycemia without clear etiology, nonislet cell tumor hypoglycemia (NICTH), which can cause severe refractory hypoglycemia, should be considered. If tumor resection is not feasible, a multifaceted therapeutic approach that includes anticancer drugs, corticosteroids, and nutrition may be required for the management of NICTH.

Acute respiratory illnesses that presented with diffuse ground-glass opacities (GGOs) on chest computed tomography (CT) scan suggest the diagnosis of coronavirus disease 2019 (COVID-19). However, many other diseases show similar CT findings, which often offer a difficult differential diagnosis. Here, we report a case of humidifier lung, a rare phenotype of hypersensitivity pneumonitis (HP), which mimicked COVID-19. A 71-year-old man was admitted because of dyspnea and diffuse GGOs found on chest CT scan. Although COVID-19 was initially suspected, his symptoms rapidly improved by the next day. A medical interview revealed that he had started using an ultrasonic humidifier 1 month ago. A high-resolution CT (HRCT) scan showed ill-defined centrilobular nodules and mosaic attenuation, which are typical of HP but atypical of COVID-19. The inhalation challenge test confirmed the diagnosis of humidifier lung. History-taking of humidifier use and a precise HRCT interpretation are helpful to differentiate it from COVID-19.

Background: The senescence-associated secretory phenotype (SASP) develops due to cellular senescence during conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, studies comparing the degree of cellular senescence and SASP between COPD and IPF are limited. Furthermore, to the best of our knowledge, no study has examined cellular senescence and/or SASP in connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: To compare the degree of cellular senescence among COPD, IPF, and CTD-ILD, tissue samples from surgical lung biopsies or noncancerous tissue from lobectomy specimens of patients with lung cancer were subjected to immunostaining for p16 and p21. Double-staining for p16 and phosphorylated NF-κB was performed to verify the relationship between cellular senescence and SASP. Results: There was a greater degree of enhancement of p16 and p21 expression in patients with IPF than in those with COPD and controls. Immunostaining for p16 revealed an enhanced expression of this marker in patients with COPD compared with that in controls. No significant differences were observed in the phosphorylated NF-κB expression rate of p16-positive and p16-negative cells among patients with IPF, CTD-ILD, and COPD. Conclusions: Epithelial cells in patients with IPF express higher levels of both cellular senescence and SASP than those in patients with COPD or controls.

Fenofibrate (FF), a peroxisome proliferator‐activated receptor‐alpha (PPAR‐α) agonist and a lipid‐lowering agent, can decrease experimental pulmonary fibrosis. However, the mechanisms underlying the antifibrotic effect of FF remain unknown. Hence, this study was conducted to evaluate the effects of FF on transforming growth factor‐beta (TGF‐β)‐induced myofibroblast differentiation and activation in lung fibroblasts. The results showed that FF inhibited alpha‐smooth muscle actin (α‐SMA) and connective tissue growth factor expression, collagen production, cell motility, SMAD3 phosphorylation and nuclear translocation, and metabolic reprogramming in TGF‐β‐exposed cells. The inhibitory effect of FF did not decrease with the addition of a PPAR‐α antagonist. Moreover, the inhibitory effect given by FF could not be reproduced with the addition of an alternative PPAR‐α agonist. FF inhibited mitochondrial respiration. However, rotenone, a complex I inhibitor, did not suppress TGF‐β‐induced myofibroblast differentiation. Furthermore, the TGF‐β‐induced nuclear reduction of protein phosphatase, Mg2+/Mn2+‐dependent 1A (PPM1A), a SMAD phosphatase, was inhibited by FF. These results showed that FF suppressed TGF‐β‐induced myofibroblast differentiation and activation independent of PPAR‐α activation and impaired mitochondrial respiration. In conclusion, this study provides information on the effects of FF on anti‐TGF‐β mechanisms., Fenofibrate, a peroxisome proliferator‐activated receptor‐α (PPAR‐α) agonist and a lipid‐lowering agent, inhibits transforming growth factor‐β (TGF‐β)‐induced myofibroblast differentiation via PPAR‐α‐independent mechanisms, which probably include the upregulation of protein phosphatase, Mg2+/Mn2+‐dependent 1A, a SMAD phosphatase, leading to export of nuclear SMAD3 to cytoplasm. This study provides evidence on the effects of fenofibrate on anti‐TGF‐β actions.

Many problems regarding structure-function relationships have remained unsolved in the field of respiratory physiology. In the present review, we highlighted these uncertain issues from a variety of anatomical and physiological viewpoints. Model A of Weibel in which dichotomously branching airways are incorporated should be used for analyzing gas mixing in conducting and acinar airways. Acinus of Loeschcke is taken as an anatomical gas-exchange unit. Although it is difficult to define functional gas-exchange unit in a way entirely consistent with anatomical structures, acinus of Aschoff may serve as a functional gas-exchange unit in a first approximation. Based on anatomical and physiological perspectives, the multiple inert-gas elimination technique is thought to be highly effective for predicting ventilation-perfusion heterogeneity between acini of Aschoff under steady-state condition. Changes in effective alveolar PO2, the most important parameter in classical gas-exchange theory, are coherent with those in mixed alveolar PO2 decided from the multiple inert-gas elimination technique. Therefore, effective alveolar-arterial PO2 difference is considered useful for assessing gas-exchange abnormalities in lung periphery. However, one should be aware that although alveolar-arterial PO2 difference sensitively detects moderately low ventilation-perfusion regions causing hypoxemia, it is insensitive to abnormal gas exchange evoked by very low and high ventilation-perfusion regions. Pulmonary diffusing capacity for CO (DLCO) and the value corrected for alveolar volume (VAV), i.e. DLCO/VAV (KCO), are thought to be crucial for diagnosing alveolar-wall damages. DLCO-related parameters have higher sensitivity to detecting abnormalities in pulmonary microcirculation than those in the alveolocapillary membrane. We would like to recommend four categories derived from combining behaviors of DLCO with those of KCO for differential diagnosis on anatomically morbid states in alveolar walls: type-1 abnormality defined by decrease in both DLCO and KCO; type-2 abnormality by decrease in DLCO but increase in KCO; type-3 abnormality by decrease in DLCO but restricted rise in KCO; and type-4 abnormality by increase in both DLCO and KCO.

Classical regression equations of spirometric parameters are not applicable for diagnosing spirometric abnormalities in adipotic adults

About a half of all patients with relapsing polychondritis show airway involvement, which is a major cause of morbidity and mortality from this disease. FDG‐PET/CT is useful in the differential diagnosis of relapsing polychondritis from asthma.

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO2 affects adipocyte differentiation (adipogenesis) and maturation (hypertrophy). Human visceral or subcutaneous preadipocytes were grown to confluence and then induced to differentiate to adipocytes under hypocapnia, normocapnia, and hypercapnia with or without hypoxia. Adipogenesis was also induced under intermittent or sustained hypercapnia. Differentiated adipocytes were maintained to maturity under normocapnia or hypercapnia. Our main findings are as follows: (1) hypercapnia accelerated adipogenesis in visceral and subcutaneous preadipocytes, whereas hypocapnia inhibited adipogenesis; (2) hypercapnia did not affect adipocyte hypertrophy; (3) hypercapnia-accelerated adipogenesis was independent of extracellular acidosis, oxygen concentr...

Background Oral mite anaphylaxis (OMA) is a syndrome characterized by severe allergic manifestations occurring in atopic patients shortly after the intake of foods made with mite-contaminated wheat flour. A history of atopic disease has been identified as one of risk factors for the development of OMA. This is the report that OMA was induced by the ingestion of Korean pancake prepared with commercial mixed wheat flour contaminated with mites. Case presentation A 15-year-old Japanese girl with a history of atopic asthma and dermatitis was admitted to the emergency department with the anaphylactic symptoms of urticaria, skin flushing, throat discomfort, acute dyspnea and severe wheezing that developed shortly after the ingestion of home-cooked buchimgae (Korean pancake) prepared with commercial mixed wheat flour. The ingredients in the buchimgae were eggs, shrimps and chopped Chinese chives, but the girl had previously consumed these individual ingredients without incident. Microscopic examination of the mixed wheat flour revealed the presence of large numbers of live dust mites. The patient's serum specific IgE analysis was positive for antibodies to dust mite allergens. From these findings, the anaphylactic episode in this patient was concluded to be the result of ingestion of mixed wheat flour contaminated with mites. Conclusions OMA was induced by the ingestion of wheat flour contaminated with mites. Physicians should be aware of this clinical picture, particularly in the case with risk factors, and recommend that wheat flour should be stored in a refrigerator to prevent mite proliferation and the development of OMA., Highlights • Oral mite anaphylaxis (OMA) is a syndrome characterized occurring after the intake of foods made with mite-contaminated wheat flour.

Inflammatory myofibroblastic tumors (IMTs) belong to an intermediate group of soft-tissue tumors, they are relatively rare but exhibit a wide range of pathologies, from benign to malignant. At present, no standard treatment has been established, however, it is known to be important to determine the grade of malignancy of the tumor, prior to treatment. The present study reports a 73-year-old female patient with no clinical manifestations, who, when examined radiographically at a health check exhibited bilateral thoracic infiltrative shadows and nodular shadows by chest CT. A metastatic tumor or an organizing pneumonia were suspected. Blood examination showed no abnormal findings, and a pathological diagnosis of IMT was given from the histological findings of the tissue extracted by video-assisted thoracic surgery. Histological analysis established the lack of expression of anaplastic lymphoma kinase (ALK1) and immunoglobulin subtype G4 (IgG4). Alteration of the radiological shadows was observed over several weeks, and after concluding that chronic inflammation was worsening the patient's condition, clarithromycin was administered as a long-term macrolide therapy. The IMT decreased in size, and eight months later it had almost resolved. The patient was last reported to be maintaining a stable condition with no relapse. Some IMT cases have malignant pathology, and should be carefully followed-up. However, in the present case, where the IMT is both ALK1-negative and IgG4-negative, its biological immune responsiveness appears to differ from positive cases, and an inflammatory response was predominant. Clarithromycin, has immunomodulatory and anti-inflammatory effects and appeared to be effective in treating the IMT of the patient in the present study.

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO

Cancer cells utilize aerobic glycolysis and proliferate continuously beyond the capacity of their blood supply, leading to microenvironmental stresses such as hypoxia, nutrient (glucose) deprivation and extracellular acidosis. We have previously showed that extracellular acidosis prevents glucose starvation-induced death of lung cancer cells by reducing glycolytic energy production and de novo protein/RNA synthesis that consume ATP (AACR 2018). This acidosis-dependent, glucose starvation-resistant, and ATP-saving phenotype is thought to serve as an adaptive response to glucose deprivation in cancer cells to survive an energy-restricted tumor microenvironment. In the present study, we screened small-molecule inhibitors to explore therapeutic reagents that can exert cytotoxicity against the glucose starvation-resistant phenotype in the lung cancer cell lines, A549 and H1299 cells. Among the various inhibitors tested, we found that ESI-09 and HJC0197, known as inhibitors of the exchanger protein directly activated by cAMP (EPAC), reduced the cellular ATP levels and survival under glucose deprivation stress under both acidic (pH 6.8) and neutral (pH 7.4) conditions. Interestingly, the ATP-reducing effect of ESI-09 and HJC0197 was not due to inhibition of the EPAC function, because the effect cannot be reproduced with other EPAC inhibitors, such as CE3F4, EPAC5376753 and ESI-05. Rather, the effect of ESI-09 and HJC0197 was attributed to their previously unknown action of uncoupling the mitochondrial electron transport chain (ETC). We found that ESI-09 and HJC0197 induced mitochondrial proton leak, causing ATP deficiency and cell death via the following three mechanisms: 1) decreased mitochondrial ATP production due to ETC uncoupling, 2) increased ATP consumption resulting from reversal of F0/F1-ATPsynthase/ATPase to maintain the mitochondrial membrane potential, and 3) glucose deficiency as a result of increased glucose consumption due to a compensatory stimulation of glycolytic ATP production. The energy-saving phenotype of cancer cells is thought to serve as an adaptive strategy that allows cell survival in an energy-restricted, acidic tumor microenvironment. Our results suggest that ESI-09 and HJC0197 disrupt bioenergetic tumor metabolism for energy homeostasis in both acidic and neutral microenvironment, and may exert a therapeutic effect against the starvation-resistant phenotype of cancer cells. The complete chemical structures of ESI-09 and HJC0197 will be divulged at the time of the presentation at the meeting. Citation Format: Yuki Iwai, Ryota Kikuchi, Hiroyuki Nakamura, Nobuyuki Koyama, Koichi Hagiwara, Kazutetsu Aoshiba. ESI-09 and HJC0197, known EPAC inhibitors, sensitize lung cancer cells to glucose starvation by uncoupling mitochondrial electron transport, leading to bioenergetic crisis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 800.

Enhancer of zeste homolog 2 (EZH2) is a catalytic component of polycomb repressive complexes, promotes tumor progression and metastasis. Expression levels of EZH2 are associated with clinical outcomes in a variety of tumors. High expression levels of EZH2 have been reported in cell lines and tissues of small cell lung cancer (SCLC), which is characterized by its invasiveness and metastatic potentials. Epithelial-mesenchymal transition (EMT) is well recognized to contribute to aggressiveness of SCLC, and microRNA (miRNA) is known to be associated with both EMT and the biological characteristics of SCLC. The aim of this study was to identify a novel miRNA defining EZH2-assciated EMT and tumor aggressiveness in SCLC. Immunohistochemistry and quantitative PCR showed that EZH2 expressions levels were decreased in three types of SCLC cell lines and tumor tissues from 34 patients with SCLC. Small interfering RNA (siRNA) against EZH2 suppressed its expression and EMT in SBC3 and SBC5 cell lines, both of which had high EZH2 expression levels as SCLC cell lines. Comprehensive miRNA expression analysis was used to compare changes of miRNA expression between EZH2 siRNA-transfected cells and mock-transfected cells. As a result, miR-4448 expression was significantly decreased in SBC3 and SBC5 cells transfected with EZH2 siRNA. Cell growth assay and cell invasion assay revealed that overexpression of miR-4448 inhibited cellular proliferation and invasion potential. Furthermore, we confirmed that overexpression of miR-4448 abrogated EMT and decreased EZH2 expression. In conclusion, EZH2 and miR-4448 mutually suppressed these expressions and functions, which was associated with tumor progression via EMT in SCLC. The findings of this study suggest that miR-4448 may play a crucial role in the biological characteristics of SCLC. Citation Format: Nobuyuki Koyama, Yuichi Ishikawa, Yuki Iwai, Kazutetsu Aoshiba, Hiroyuki Nakamura, Koichi Hagiwara. Mutual negative regulation of EZH2 and miR-4448 for tumor progression via epithelial mesenchymal transition in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 766.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lung and whole body caused mainly by tobacco smoking. Patients with advanced COPD are in a state of undernutrition, referred to as pulmonary cachexia; the exercise performance and quality of life (QOL) of these patients are deteriorated, the vital prognosis is unfavorable, and the medico-economic burden posed by poorly nourished COPD patients is high. The mainstays of COPD treatment are pharmacotherapy, mainly with bronchodilators, and non-pharmacotherapeutic approaches such as respiratory rehabilitation and nutrition counseling. Nutritional supplement therapy, consisting primarily of high calorie intake, has been demonstrated to be effective for maintaining and improving the muscle strength and exercise tolerance in poorly nourished COPD patients. The efficacy of intake of various nutrients, besides a high calorie intake, for amelioration of the disease state of COPD has also been reported. The roles of adipokines in the pathophysiology of COPD have begun to receive attention recently, and not only their regulatory effects on appetite and nutritional status, but also their influence on systemic inflammation have been increasingly clarified. We review the papers on COPD and nutrition and discuss the role of nutritional supplement therapy in the treatment of COPD.

Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a two-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A more severe degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and the large amounts of reactive oxygen species and reactive nitrogen species released from inflammatory cells are likely to induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely to be activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterised by mutually reinforcing inflammation and DNA damage, may cause the inflammation in COPD patients to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer.

Introduction: While tissue hypoxia is known to play a critical role in the process of vascular injury and repair, the effect of hypercapnia on this process remains uncertain. We investigated whether hypercapnia might influence endothelial cell wound healing under the influence of hypoxia. Materials and Methodology: Monolayers of human umbilical venous endothelial cells (HUVECs) were scratch-wounded and incubated under different levels of O2, CO2, and pH in the environment. Results: Inhibition of wound healing was observed in the HUVEC monolayers under the hypoxic condition as compared to the normoxic condition. Both hypercapnic acidosis and buffered hypercapnia, but not normocapnic acidosis improved the rate of wound healing under the influence of hypoxia. The beneficial effect of hypercapnia was associated with stimulation of cell proliferation, without effects on cell adhesion, migration or apoptosis. On the other hand, the stimulatory effect of hypercapnia on wound healing and cell proliferation was not noted under normoxic conditions. Conclusion: These results suggest that hypercapnia, rather than acidosis per se, accelerated the wound healing in HUVEC monolayers cultured under hypoxic conditions. The effect of hypercapnia on wound healing was due, at least in part, to the stimulation of cell proliferation by hypercapnia.

Aim: To develop the novel regression equations that predict spirometric parameters (SPs) in concert with aging-specific corrections for four explanatory variables, including age, height, body weight, and fat fraction of body mass. Subjects: A large cohort of nonsmoking, non-obese, healthy adults in the general population in Japan (males: 3,056, females: 6,783). Methods: Supposing that SP is described by an aging-dependent, logarithmic, additive function of age, height, body weight, and fat fraction of body mass, gender- and aging-specific regression equations predicting the forced vital capacity (FVC), forced expiratory volume after one second (FEV1), FEV1/FVC, peak expiratory flow rate (PEF), forced expiratory flow rate at 50% expiration of the FVC (FEF50), and forced expiratory flow rate at 75% expiration of the FVC (FEF75) were established. The partial regression coefficients of explanatory variables against a specific SP were decided by a step-wise, multiple-regression analysis with least-squares minimization. Results: Age and fact fraction of body mass exerted negative impacts, whereas height and body weight had positive impacts on various SPs in an aging-dependent and/or aging-independent manner. These aging-related contributions of explanatory variables were highly gender-specific. Body weight and fat fraction of body mass concurrently played an important role in prescribing the SP, particularly in females. Conclusions: The gender-specific, aging-related corrections of age, height, body weight, and fat fraction body mass are important for deciding various spirometric parameters. If the aging-dependent and/or aging-independent contributions of body weight and/or fat fraction of body mass are ignored, substantial errors emerge for the reference means and lower limits of normal of specific SPs

Exercise-training-based pulmonary rehabilitation has been confirmed to be effective in improving the activities of daily living (ADL) and relieving the dyspnea of chronic obstructive pulmonary disease (COPD) patients. Exercise training increases the antioxidant capacity of COPD patients, but since strenuous exercise and acute exercise loading have the opposite effect and increase oxidative stress, it is important to establish exercise training conditions that efficiently raise antioxidant capacity without increasing oxidative stress. Research on oxidative stress during exercise training by COPD patients has been pursued from that standpoint, but in recent years the targets of research on respirator diseases other than COPD have been expanding. In this article we will therefore review the results of research that has been conducted thus far on the effect of pulmonary rehabilitation on oxidative stress, including the results obtained at our own institution.

Bioenergetic tumor metabolism is essential to meet ATP requirements for energy homeostasis. Cancer cells utilize aerobic glycolysis and proliferate continuously beyond the capacity of blood supply. These phenotypic alterations lead to various microenvironmental stresses, such as hypoxia, nutrient (glucose) deprivation, and extracellular acidosis, to which cancer cells must metabolically adapt in order to survive and proliferate. However, compared to hypoxia, relatively little is known about the metabolic adaptations in response to glucose deprivation and acidosis. In the present study, we explored the effects of extracellular acidosis on cancer metabolism under glucose deprivation stress, as extracellular acidosis and insufficient glucose supply usually co-exist in the tumor microenvironment. To this aim, A549 lung cancer cells were treated with acidosis, glucose deprivation, or a combination. Then, cell survival, total cellular ATP turnover, relative glycolytic and mitochondrial dependency and capacity, and de novo rRNA and protein synthesis were determined. We found that acidosis (pH 6.8) inhibited ATP depletion and cell death induced by glucose deprivation. The cytoprotective effect of acidosis against glucose deprivation-induced cell death was mediated by two distinct mechanisms. First, acidosis shifted cellular ATP production from glycolysis to OXPHOS that became independent of glucose uptake but dependent on glutaminolysis and fatty acid β-oxidation. Second, acidosis reduced ATP consumption by inhibiting de novo rRNA and protein synthesis that utilizes ATP. In contrast, the protective effect of acidosis on glucose starvation-induced cell death was independent of AMPK, PI3K, ERK, and p38 MAPK. Based on this mechanistic knowledge of acidosis-dependent metabolic alterations, we tested the effect of the mitochondrial complex I inhibitor metformin on death of lung cancer cells. Metformin and a combination of rotenone and AICAR mimicking an action of metformin induced ATP depletion and cell death in glucose-free medium, but under acidosis the cytotoxic effect of metformin was significantly attenuated because overall ATP turnover was reduced under low pH. These results suggest that during acidosis, cells are forced to a reduced glycolytic energy production, but the decrease in protein synthesis and ATP requirement serves as an adaptive response to glucose deprivation stress. This acidosis-dependent, glucose starvation-resistant phenotype may provide an adaptive strategy in an energy-restricted tumor microenvironment. Our findings highlight the importance of considering the two factors, acidosis and nutrient starvation in combination to understand their contributions to tumor metabolism. Citation Format: Yuki Iwai, Ryota Kikuchi, Yasutaka Watanabe, Nobuyuki Koyama, Koichi Hagiwara, Hiroyuki Nakamura, Kazutetsu Aoshiba. Extracellular acidosis inhibits glucose starvation-induced lung cancer cell death by suppressing overall metabolic rate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2407.

Background: Alveolar cell senescence is accelerated in patients with chronic obstructive pulmonary disease (COPD). Objectives: We tested the hypothesis that alveolar cell senescence contributes to the chronic inflammation that affects the lungs of COPD patients. Methods: We exposed alveolar type II-like epithelial (A549) cells to a G-quadruplex-interacting telomerase inhibitor in vitro to induce cellular senescence and analyzed the production of proinflammatory cytokines and the activation of NF-ĸB. Human dermal microvascular endothelial cells (HDMECs) were serially passaged to induce replicative senescence. We also immunostained human lung tissue sections obtained from COPD patients, asymptomatic smokers and asymptomatic nonsmokers and examined correlations between type II cell senescence and inflammation. Results: Senescent A549 cells and HDMECs, whether stimulated with lipopolysaccharide or not, produced greater amounts of IL-6, IL-8 and TNF-α, which paralleled NF-ĸB activation, than did presenescent cells. There were positive correlations between the percentages of senescent type II cells that expressed p16INK4a and the percentages of type II cells that expressed phosphorylated NF-ĸB. The lung tissue of the COPD patients contained higher percentages of proinflammatory senescent type II cells that co-expressed p16INK4a and phosphorylated NF-ĸB than the tissue from asymptomatic smokers and asymptomatic nonsmokers. Higher percentages of p16INK4a-positive senescent type II cells than of p16INK4a-negative presenescent type II cells were positive for phosphorylated NF-ĸB. Conclusions: Senescence of alveolar epithelial cells is associated with functional alterations of the cells to a proinflammatory phenotype and may contribute to the pathogenesis of COPD.

We report herein that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure but also apoptosis, cellular proliferation, and cellular senescence. Cellular proliferation compensates for increased alveolar cell apoptosis in patients with chronic obstructive pulmonary disease (COPD). However, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. As a result, alveolar cells disappear and the emphysematous lesions progress. At the same time, cellular senescence is believed to induce inflammation. More specifically, senescent alveolar cells induce inflammation by producing various inflammatory cytokines in tissue. Lymphocytes and Clara cells may also age more rapidly in the lungs of patients with COPD. Lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and Clara cell senescence may impair airway regeneration as well as sustain airway inflammation. Thus, cellular senescence may be involved in arrested tissue repair, chronic inflammation, and increased susceptibility to infection, which are the typical features of COPD.