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The aim of this study was to assess the association of serum C-reactive protein (CRP) levels with outcomes in 81 patients with epidermal growth factor receptor (EGFR)-mutated non-small cell...

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.

Appropriate drug treatment for smoking asthmatics is uncertain because most smokers with asthma are less sensitive to treatment with glucocorticoids compared with non-smokers with asthma. We hypothesized that roflumilast (Rof), a selective phosphodiesterases-4 inhibitor regarded as an add-on therapy for chronic obstructive pulmonary disease, might be more effective than glucocorticoids for improving asthma in smokers. To investigate this hypothesis, we compared the therapeutic effects of dexamethasone (Dex) and Rof in a mouse model of ovalbumin-induced asthma with or without concurrent cigarette smoke (CS) exposure for 2 weeks. We found that recurrent asthma attacks increased lung tissue resistance. CS exposure in asthmatic mice decreased the central airway resistance, increased lung compliance, and attenuated airway hyper-responsiveness (AHR). CS exposure in asthmatic mice also increased the number of neutrophils and macrophages in the bronchoalveolar fluid. Treatment with Dex in asthmatic mice without CS exposure reduced airway resistance, AHR and airway eosinophilia. In asthmatic mice with CS exposure, however, Dex treatment unexpectedly increased lung tissue resistance and restored AHR that had been otherwise suppressed. Dex treatment in asthmatic mice with CS exposure inhibited eosinophilic inflammation but conversely exacerbated neutrophilic inflammation. On the other hand, treatment with Rof in asthmatic mice without CS exposure reduced airway resistance and airway eosinophilia, although the inhibitory effect of Rof on AHR was unremarkable. In asthmatic mice with CS exposure, Rof treatment did not exacerbate lung tissue resistance but modestly restored AHR, without any significant effects on airway inflammation. These results suggest that CS exposure mitigates sensitivity to both Dex and Rof. In asthmatic mice with CS exposure, Dex is still effective in reducing eosinophilic inflammation but increases lung tissue resistance, AHR and neutrophilic inflammation. Rof is ineffective in improving lung function and inflammation in asthmatic mice with CS exposure. This study did not support our initial hypothesis that Rof might be more effective than glucocorticoids for improving asthma in smokers. However, glucocorticoids may have a detrimental effect on smoking asthmatics.

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.

(1) To establish the general equation that describes relationship of DM(1) Given that "true" θ

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

In Europe and America, the newly-developed, simultaneous measurement of diffusing capacity for CO (DLCO) and NO (DLNO) has replaced the classic DLCO measurement for detecting the pathophysiological abnormalities in the acinar regions. However, simultaneous measurement of DLCO and DLNO is currently not used by Japanese physicians. To encourage the use of DLNO in Japan, the authors reviewed aspects of simultaneously-estimated DLCO and DLNO from previously published manuscripts. The simultaneous DLCO-DLNO technique identifies the alveolocapillary membrane-related diffusing capacity (membrane component, DM) and the blood volume in pulmonary microcirculation (VC); VC is the principal factor constituting the blood component of diffusing capacity (DB,DB=θ·VC where θ is the specific gas conductance for CO or NO in the blood). As the association velocity of NO with hemoglobin (Hb) is fast and the affinity of NO with Hb is high in comparison with those of CO, θNO can be taken as an invariable simply determined by diffusion limitation inside the erythrocyte. This means that θNO is independent of the partial pressure of oxygen (PO2). However, θCO involves the limitations by diffusion and chemical reaction elicited by the erythrocyte, resulting in θCO to be a PO2-dependent variable. Furthermore, DLCO is determined primarily by DB (∼77%), while DLNO is determined equally by DM (∼55%) and DB (∼45%). This suggests that DLCO is more sensitive for detecting microvascular diseases, while DLNO can equally identify alveolocapillary membrane and microcirculatory abnormalities.

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...

Chronic obstructive pulmonary disease (COPD) is often associated with co-morbidities. Metabolic disorders like hyperlipidemia and diabetes occur also in underweight COPD patients, although the mechanism is uncertain. Subcutaneous adipose tissue (SAT) plays an important role in energy homeostasis, since restricted capacity to increase fat cell number with increase in fat cell size occurring instead, is associated with lipotoxicity and metabolic disorders. The aim of this study is to show the protective role of SAT for the metabolic disorders in pulmonary emphysema of a murine model. We found ectopic fat accumulation and impaired glucose homeostasis with wasting of SAT in a murine model of elastase-induced pulmonary emphysema (EIE mice) reared on a high-fat diet. ONO-AE1-259, a selective E-prostanoid (EP) 2 receptor agonist, improved angiogenesis and subsequently adipogenesis, and finally improved ectopic fat accumulation and glucose homeostasis with restoration of the capacity for storage of surplus energy in SAT. These results suggest that metabolic disorders like hyperlipidemia and diabetes occured in underweight COPD is partially due to the less capacity for storage of surplus energy in SAT, though the precise mechanism is uncertained. Our data pave the way for the development of therapeutic interventions for metabolic disorders in emphysema patients, e.g., use of pro-angiogenic agents targeting the capacity for storage of surplus energy in the subcutaneous adipose tissue.

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.

Rationale: Wasting of the subcutaneous adipose tissue (SAT) is one of the clinical characteristics of patients with pulmonary emphysema, although visceral fat accumulation has been also reported. The capacity of SAT to store the surplus lipid would determine the overflow of lipid, resulting metabolic disorders like visceral fat accumulation. The aim of this study is to explore subcutaneous and vesceral adipocytes in patients with pulmonary emphysema. Methods: We evaluated formalin-fixed, paraffin-embedded human subcutaneous and visceral adipose tissue samples obtained from smokers with pulmonary emphysema and from healthy smokers. The adipocyte size w determined on hematoxylin & eosin-stained paraffin sections by quantifying the actual area of discrete adipocytes. The subcutaneous and visceral fat area were assessed using cross-sectional CT scans at the umbilicus level. Results: The areas of SAT were significantly decreased in smokers with pulmonary emphysema as compared to healthy smokers, even though the average adipocyte sizes were similar, suggesting reduced number of subcutaneous adipocytes in smokers with pulmonary emphysema. The areas of visceral adipose tissue were similar between smokers with pulmonary emphysema and healthy smokers, even though the average viseceral adipocyte sizes in smokers with emphysema tended to be increased as compared to healthy smokers, suggesting reduced number and subsequent hypertrophy of viseceral adipocytes in smokers with emphysema. Conclusion: This study showed the reduced number of subcutaneous adipocytes and hypertrophy of visceral adipocytes due to impaired capacity of SAT to store the surplus lipid in patients with pulmonary emphysema.

Recent evidence suggests that epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of airway obstructive diseases, such as chronic obstructive pulmonary disease, asthma and bronchiolitis obliterans syndrome after lung transplantation. However, whether EMT occurs in an experimental model of airway fibrosis is not well known. We explored evidence of EMT in a murine model of airway fibrosis induced by repeated exposure to naphthalene. Mice were administered intraperitoneal injections of naphthalene or corn oil vehicle once weekly for 14 consecutive weeks. The animals were sacrificed 5days after the final injection of naphthalene or corn oil vehicle. EMT was evaluated in lung tissue sections using immunohistochemistry and immunofluorescence. Repeated naphthalene exposure induced loss of club cells, hyperplasia of epithelial cells and peribronchial fibrosis. However, we did not find any loss of E-cadherin expression or any acquisition of vimentin, S100A4 or αSMA in epithelial cells in control or naphthalene-exposed mice. These results suggest that EMT does not contribute significantly to naphthalene-induced airway fibrosis in mice.

Objective Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to glucose shortage is essential to maintain tumor cells’ survival because of their high glucose requirement. This study evaluated the hypothesis that acidosis might promote tumor survival during glucose shortage and if so, explored a novel drug targeting metabolic vulnerability to glucose shortage. Methods Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model. Results Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anti-cancer compound that inhibited cancer cells under low-glucose conditions even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycle of mitochondrial respiration, leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung cancer engraft mice. Conclusions This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anti-cancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower-than-normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types., Highlights • Tumor cells experience hypoxia, acidosis, and glucose shortage. • Tumor acidosis promotes metabolic adaptation to glucose shortage. • ESI-09, a known EAPC inhibitor, is a novel and safe mitochondrial uncoupler. • ESI-09 kills tumor cells during glucose shortage, even under acidosis conditions. • ES-09 targets metabolically dormant and chemotherapy-resistant tumor cells.

Objectives (1) To establish the general equation that describes relationship of DMCO/Vc versus DLNO/DLCO under conditions with no functional heterogeneities. (2) To examine the effects of functional heterogeneities, including parallel and series (stratified) heterogeneities, on DLNO/DLCO. Results and discussions: (1) Given that “true” θNO in pulmonary capillaries is represented by surface absorption-related θNO, relationship between DMCO/Vc and DLNO/DLCO does not differ significantly from that obtained on premise of infinite θNO. DLNO/DLCO decided physiologically may mirror morphometric DMCO/Vc actually working for gas exchange but not “total” morphometric ratio of DMCO/Vc. (2) There are three parallel heterogeneities that affect diffusing capacity (D)-related parameters. Of them, only the heterogeneity of D/VA, where VA is alveolar volume, underestimates DLCO and DLNO. DLNO/DLCO does not alleviate negative impact of D/VA heterogeneity, indicating that DMCO/Vc estimated from DLNO/DLCO does not mirror “true” morphometric DMCO/Vc in diseased lungs with D/VA maldistribution. (3) Stratified heterogeneity underrates morphometric DMCO, DMNO, and DMNO/DMCO maximally by 1.4 %, 2.8 %, and 1.4 %, respectively, under conditions similar to single-breath D measurements, suggesting that effect of stratified heterogeneity on D measures is no longer needed to be considered in normal subjects but may be in patients having lung diseases with destructive lesions of acinar structures.

Objectives To propose new physical constants for NO and CO (Krogh diffusion constant ratio (KDNO/CO) and specific blood conductance for NO (θNO)) for calculating DMCO and Vc, according to Roughton-Forster’s equation (Roughton and Forster, J. Appl. Physiol. 11: 290–302, 1957) from simultaneous DLNO and DLCO measurements. Results and conclusions (1) The Graham’s law is unacceptable for determining KDNO/CO because CO does not fulfil all the conditions of an “ideal” gas. We have re-estimated KDNO/CO in a new way based on difference in molar volumes of two gases (molar volume theory). The KDNO/CO thus decided is 2.34. (2) θNO measured with rapid-reaction, constant-flow method by Carlsen and Comroe (J. Gen. Physiol. 42: 83–107, 1958) may be underestimated by about 40 % due to unstirred water layer surrounding the erythrocyte. (3) Erythrocyte θO2 can be harvested from O2 release kinetics in presence of high concentration of dithionite, which effectively removes the unstirred water layer-elicited effect. Multiplication of erythrocyte θO2 by erythrocyte KDNO/O2 equals erythrocyte θNO, the value of which is 6.2 mL/min/mmHg/(mL⋅blood). According to the concepts of Kang et al. (RESPNB. 241: 62–71, 2017) and Borland et al. (RESPNB. 241: 58–61, 2017), in vitro θNO decided from rapid-mixing experiments may mirror bulk absorption of NO by erythrocytes. (4) In pulmonary capillaries, NO uptake takes place predominantly in the surface rim of the erythrocyte. This surface absorption of NO increases the θNO 10-fold versus bulk absorption of NO to about 60 mL/min/mmHg/(mL⋅blood).