lung-fixation-under-constant-pressure-for-evaluation-emphysema

Lung Fixation under Constant Pressure for Evaluation of Emphysema in Mice

Emphysema is a significant feature of chronic obstructive pulmonary disease (COPD). Studies involving an emphysematous mouse model require optimal lung ...

Juntendo University

Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease characterized with proliferation of abnormal smooth muscle-like cells (LAM cells) in the lungs and along axial lymphatics. Proliferation of LAM cells are considered to be driven by dysregulated mTORC1 signaling, that is caused by mutations in either the TSC1 or TSC2 gene in LAM cells. The MILES trial has successfully demonstrated that sirolimus, a mTORC1 inhibitor, can stabilize pulmonary function in LAM, but its effect disappears once sirolimus is discontinued. Limited ability of sirolimus may be due to concomitant activation of autophagy in LAM cells when mTORC1 activity is suppressed by sirolimus. Recently animal models for LAM have been independently established by several groups, which may provide a platform for developing drugs interfering various steps in disease progression.

[Current understanding and perspectives of lymphangioleiomyomatosis].

Pleural mesothelioma is an aggressive tumor, commonly caused by exposure to asbestos. The prognosis of mesothelioma remains disappointing despite multimodal treatment. We reported previously that N-ERC/mesothelin could be a useful biomarker for the early diagnosis of pleural mesothelioma and developed an enzyme-linked immunosorbent assay (ELISA) system for its detection. However, the reproducibility of our previous 7-16 ELISA system has been revealed to be unsatisfactory. To measure N-ERC/mesothelin more precisely, we developed a new 7-20 ELISA system. The subjects of this study were patients who were referred to our department with suspected pleural mesothelioma. The current study demonstrated that the newly established 7-20 ELISA system improved the sensitivity and specificity for diagnosing pleural mesothelioma compared with the previous system. Moreover, the 7-20 ELISA system showed better reproducibility and displayed the tendency of both higher sensitivity and higher specificity in plasma than in serum. Particularly for the epithelioid type, the area under the curve (AUC) and the diagnostic accuracy of N-ERC/mesothelin were excellent; the AUC was 0.91, the sensitivity was 0.95, and the specificity was 0.76 in plasma. In conclusion, assessment of N-ERC/mesothelin with our newly established 7-20 ELISA system is clinically useful for the precise diagnosis of pleural mesothelioma. 

Newly established ELISA for N-ERC/mesothelin improves diagnostic accuracy in patients with suspected pleural mesothelioma.

Poor or short sleep and the presence of snoring indicative of sleep-disordered breathing (SDB) have been associated with behavioral problems in school-aged children. We examined the relationship between SDB, sleep duration, obesity risk, and behavioral characteristics in Japanese elementary school students using a large-scale survey.

Sleep Duration, Snoring Prevalence, Obesity, and Behavioral Problems in a Large Cohort of Primary School Students in Japan.

This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.

Protein-losing Enteropathy Caused by Intestinal or Colonic Lymphangiectasia Complicated by Sporadic Lymphangioleiomyomatosis: A Report of Two Cases.

Chronic obstructive pulmonary disease (COPD) is predominantly a cigarette smoke (CS)-triggered disease with features of chronic systemic inflammation. Oxidants derived from CS can induce DNA damage and stress-induced premature cellular senescence in the respiratory system, which play significant roles in COPD. Therefore, antioxidants should provide benefits for the treatment of COPD; however, their therapeutic potential remains limited owing to the complexity of this disease. Recently, molecular hydrogen (H) has been reported as a preventive and therapeutic antioxidant. Molecular H can selectively reduce hydroxyl radical accumulation with no known side effects, showing potential applications in managing oxidative stress, inflammation, apoptosis, and lipid metabolism. However, there have been no reports on the efficacy of molecular H in COPD patients. In the present study, we used a mouse model of COPD to investigate whether CS-induced histological damage in the lungs could be attenuated by administration of molecular H. We administered H-rich pure water to senescence marker protein 30 knockout (SMP30-KO) mice exposed to CS for 8 weeks. Administration of H-rich water attenuated the CS-induced lung damage in the SMP30-KO mice and reduced the mean linear intercept and destructive index of the lungs. Moreover, H-rich water significantly restored the static lung compliance in the CS-exposed mice compared with that in the CS-exposed H-untreated mice. Moreover, treatment with H-rich water decreased the levels of oxidative DNA damage markers such as phosphorylated histone H2AX and 8-hydroxy-2'-deoxyguanosine, and senescence markers such as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1, and β-galactosidase in the CS-exposed mice. These results demonstrated that H-rich pure water attenuated CS-induced emphysema in SMP30-KO mice by reducing CS-induced oxidative DNA damage and premature cell senescence in the lungs. Our study suggests that administration of molecular H may be a novel preventive and therapeutic strategy for COPD.

Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice.

Senescent cells accumulate in tissues during aging and are considered to underlie several aging-associated phenotypes and diseases. We recently reported that the elimination of p19 -expressing senescent cells from lung tissue restored tissue function and gene expression in middle-aged (12-month-old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no direct evidence to show that cellular senescence promotes the pathology of emphysema, and the involvement of senescence in the development of this disease has yet to be clarified. We herein demonstrated that p19 facilitated the development of pulmonary emphysema in mice. The elimination of p19 -expressing cells prevented lung tissue from elastase-induced lung dysfunction. These effects appeared to depend on reduced pulmonary inflammation, which is enhanced after elastase stimulation. Furthermore, the administration of a senolytic drug that selectively kills senescent cells attenuated emphysema-associated pathologies. These results strongly suggest the potential of senescent cells as therapeutic/preventive targets for pulmonary emphysema.

Elimination of p19 -expressing cells protects against pulmonary emphysema in mice.

Cigarette smoke (CS) exposure causes an abnormal inflammatory response, which can result in chronic obstructive pulmonary disease (COPD). Previous studies show that this disorder predominantly occurs in peripheral or small-airway areas, whereas the same condition has not been identified in the larger airways during the course of COPD. However, the different biochemical and genetic alterations occurring in response to CS exposure among airway epithelial cells from different sites in the lungs have not been fully investigated.

Regional heterogeneity in response of airway epithelial cells to cigarette smoke.

The association between nocturnal enuresis (NE) and sleep disordered breathing (SDB) has been repeatedly reported, but has primarily been focused on clinical cohorts. The purpose of this study, was to assess whether SDB-related symptoms such as snoring and unrefreshing sleep in the morning are associated with NE in a large-scale community school-based survey.

Nocturnal enuresis and sleep disordered breathing in primary school children: Potential implications.

The aim of this study was to examine the prevalence of sleep-disordered breathing (SDB) in women working in the field of aged care in Japan.

Article	Year
[Current understanding and perspectives of lymphangioleiomyomatosis]. Nihon rinsho. Japanese journal of clinical medicine\| PubMed ID: 23855221	2013
Newly established ELISA for N-ERC/mesothelin improves diagnostic accuracy in patients with suspected pleural mesothelioma. Cancer medicine\| PubMed ID: 25045139	2014
Sleep Duration, Snoring Prevalence, Obesity, and Behavioral Problems in a Large Cohort of Primary School Students in Japan. Sleep\| PubMed ID: 28364432	2017
Protein-losing Enteropathy Caused by Intestinal or Colonic Lymphangiectasia Complicated by Sporadic Lymphangioleiomyomatosis: A Report of Two Cases. Internal medicine (Tokyo, Japan)\| PubMed ID: 28420844	2017
Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice. Biochemical and biophysical research communications\| PubMed ID: 28807355	2017
Elimination of p19 -expressing cells protects against pulmonary emphysema in mice. Aging cell\| PubMed ID: 30058137	2018
Regional heterogeneity in response of airway epithelial cells to cigarette smoke. BMC pulmonary medicine\| PubMed ID: 30180847	2018
Nocturnal enuresis and sleep disordered breathing in primary school children: Potential implications. Pediatric pulmonology\| PubMed ID: 30203928	2018
Prevalence of sleep-disordered breathing among women working in the aged care services in Japan. International archives of occupational and environmental health\| PubMed ID: 30483875	2019

Yohei Suzuki

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