Proteomics and Machine Learning in the Prediction and Explanation of Low Pectoralis Muscle Area.

Low muscle mass is associated with numerous adverse outcomes independent of other associated comorbid diseases. We aimed to predict and understand an individual's risk for developing low muscle mass using proteomics and machine learning. We identified 8 biomarkers associated with low pectoralis muscle area (PMA). We built 3 random forest classification models that used either clinical measures, feature selected biomarkers, or both to predict development of low PMA. The area under the receiver operating characteristic curve for each model was: clinical-only = 0.646, biomarker-only = 0.740, and combined = 0.744. We displayed the heterogenetic nature of an individual's risk for developing low PMA and identified 2 distinct subtypes of participants who developed low PMA. While additional validation is required, our methods for identifying and understanding individual and group risk for low muscle mass could be used to enable developments in the personalized prevention of low muscle mass.

Non-exercise Activity Thermogenesis Correlated With Clinical Parameters in Patients With or At-Risk for Chronic Obstructive Pulmonary Disease (COPD): A Pilot Study.

BACKGROUND: Attention to physical activity has grown in patients with chronic obstructive pulmonary disease (COPD), as it serves as a robust indicator for mortality associated with COPD. Non-exercise activity thermogenesis (NEAT) is the energy expenditure due to physical activities besides active sports-like exercises and resistance training in daily life, and decreased NEAT may be related to physical inactivity in patients with COPD. We examined whether NEAT assessed using a questionnaire reflects clinical parameters in patients with or at risk for COPD. METHODS: The study participants consisted of 36 male patients (COPD=28; stage1=6, stage2=14, stage3/4=8, and at-risk for COPD=8) older than 50 years of age. The participants underwent anthropometric measurements, lung function testing, a six-minute walk test, muscle strength testing, and questionnaires, e.g., the COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scale, and Hospital Anxiety and Depression Scale. Image analysis with chest computed tomography (CT) included the number of trunk muscles, bronchial wall thickening, and emphysema (percentage of the lung field occupied by low attenuation area <-950 HU). We evaluated the relationship between these clinical parameters and NEAT questionnaire scores using Pearson correlation analysis and the Tukey-Kramer test. RESULTS: The NEAT score was correlated with the severity of airflow limitation and airway wall thickness measured by chest CT, symptoms evaluated by the mMRC dyspnea scale and CAT, and inspiratory muscle strength and pectoralis muscle area assessed by CT. CONCLUSION: Our study revealed the significance of NEAT as a valuable indicator in assessing the health status of patients with or at risk for COPD. The NEAT score was correlated with various clinical traits, suggesting that incorporating NEAT assessments using a questionnaire can contribute to a comprehensive understanding of the clinical condition in these patients. Further large-scale studies are warranted to validate and generalize these findings across diverse COPD populations.

Differential impacts between fat mass index and fat-free mass index on patients with COPD.

BACKGROUND: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients. METHODS: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared. RESULTS: The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (KCO). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores. CONCLUSION: FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.

Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea.

STUDY OBJECTIVES: Poor adherence to continuous positive airway pressure (CPAP) has been a critical issue in treating obstructive sleep apnea. Because long-term CPAP adherence may be established shortly after treatment begins, early intervention is essential. This study aimed to identify the potential factors affecting CPAP therapy adherence during diagnostic polysomnography and auto CPAP titration polysomnography. METHODS: This retrospective observational study included 463 patients with obstructive sleep apnea who underwent consecutive diagnostic polysomnography and titration polysomnography. We recorded their demographic, anthropometric, and lifestyle factors and obtained self-reported comments regarding their sleep status following both polysomnography evaluations. CPAP adherence was evaluated following 3 months of treatment. RESULTS: A total of 312 patients (67.4%) fulfilled the criteria for good adherence. Each patient's CPAP adherence was categorized as "poor" (< 4 hours/night or <70% of nights), "good" (≥ 4 hours/night and ≥ 70% of nights), or "excellent" (≥ 6 hours/night and ≥ 80% of nights). There were no significant differences in arterial oxyhemoglobin saturation measured by pulse oximetry and apnea-hypopnea index during diagnostic polysomnography among 3 groups. The polysomnographic evaluations indicated that patients with better adherence displayed more significant improvements in sleep parameters, including apnea-hypopnea index, sleep efficacy, sleep latency, and sleep architecture, which were correlated with an improvement in self-reported sleep quality. CONCLUSIONS: Polysomnographic evaluations enabled CPAP adherence prediction and a comparison of self-reported sleep quality with and without CPAP; CPAP adherence led to improvements in polysomnographic parameters. Our findings suggest that titration polysomnography and self-reported sleep improvement with CPAP could be used for adherence prediction in clinical practice. CITATION: Shirahata T, Uchida Y, Uchida T, et al. Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea. J Clin Sleep Med. 2023;19(8):1465-1473.

Impact of non-exercise activity thermogenesis on physical activity in patients with COPD.

Physical inactivity is associated with comorbidities and mortality in chronic obstructive pulmonary disease (COPD) patients. Although non-exercise activity thermogenesis (NEAT) is important for evaluating the physical activity level (PAL) of patients with chronic diseases, it has not yet been assessed in COPD patients. This study included male patients with COPD (n = 28) and high risk for COPD (n = 8). Total energy expenditure (TEE) and basal metabolic rate (BMR) were measured using the doubly labeled water (DLW) method and indirect calorimetry, respectively. PAL was calculated as TEE/BMR, while the NEAT was obtained from a questionnaire. Physical activity was also assessed using an accelerometer. The total NEAT score was correlated with PAL (r = 0.534, P < 0.001), while PAL was correlated more strongly with the non-locomotive NEAT score (r = 0.548, P < 0.001) than the locomotive NEAT score (r = 0.278, P = 0.10). Regarding accelerometer-obtained data, this questionnaire mainly reflected steps/day and the duration of light locomotive and non-locomotive daily activities. The NEAT score is a possible option for evaluating PAL in daily clinical practice. The present results indicated that non-locomotive activity may have a greater impact on PAL than locomotive activity in COPD patients.

Possible association of high-density lipoprotein cholesterol levels with trunk muscle deficits and decrease in energy expenditure in patients with or at risk for COPD: A pilot study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with low muscle mass and function caused by malnutrition and physical inactivity. We aimed to investigate possible associations between serum biomarkers and clinical traits including computed tomography-derived muscle measurements and energy expenditure indices in COPD. METHODS: Total energy expenditure (TEE) was measured by the doubly labeled water method, while physical activity level (PAL) was calculated as TEE/basal metabolic rate. Cross-sections and densities of pectoralis, rectus abdominis, and erector spinae muscles were measured. Serum biomarkers included adiponectin, insulin-like growth factor-1, and high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol (C). RESULTS: HDL-C levels were significantly correlated with all muscle areas, densities, and TEE. Only LDL-C levels were correlated with PAL. CONCLUSIONS: HDL-C level was a potential biomarker for trunk muscle volumes and functions, as well as total energy expenditure in COPD.

Predicting the presence and severity of obstructive sleep apnea based on mandibular measurements using quantitative analysis of facial profiles via three-dimensional photogrammetry.

BACKGROUND: In obstructive sleep apnea (OSA), the upper airway is obstructed during sleep due to obesity and/or posterior collapse of the tongue root. Maxillofacial morphological abnormalities increase the risk of OSA in the Asian population. This study sought to elucidate whether three-dimensional (3D) photogrammetry measurements correlate with the severity of OSA irrespective of sex and degree of obesity. METHODS: A prospective pilot study was performed, in which 37 consecutive adult patients (M/F = 28/9) underwent polysomnography and 3D photogrammetry in the supine position for the diagnosis of OSA. Measurements obtained from 3D photogrammetry included mandibular width (Mw), mandibular length (Ml), mandibular depth (Md), mandibular width-length angle (Mwla), and mandibular area (Ma). The effects of sex and body mass index (BMI) on the measurements and their association with the apnea-hypopnea index (AHI) were statistically analyzed. The inter-rater reliability of the measurements was evaluated using intraclass correlation coefficients (ICC). RESULTS: Mwla (R = 0.73, p < 0.01), Mw (R = 0.39, p < 0.05), and Md (R = -0.34, p < 0.05) were significantly correlated with the severity of OSA. On multivariate analysis, Mwla (p < 0.01) and Md (p < 0.05) remained independent factors for AHI after adjusting for sex, age, BMI, and neck circumference. In addition, diagnosability analysis revealed that Mwla was useful for identifying the presence of OSA (AHI ≥5) (cutoff: 78.6°, sensitivity: 0.938, specificity: 0.800, area under the curve: 0.931). The ICC was >0.9, showing high reliability. CONCLUSIONS: This study suggests that Mwla measured using 3D photogrammetry can predict the presence of OSA and correlates with the severity of OSA, independent of obesity and sex.

Evaluation of energy intake by brief-type self-administered diet history questionnaire among male patients with stable/at risk for chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Weight loss and reduced fat-free mass are independent risk factors for mortality among patients with chronic obstructive pulmonary disease (COPD). These factors are important for determining diet therapy and examining the validity of assessment for energy intake (EI). We assessed the agreement of EI between a brief-type self-administered diet history questionnaire (BDHQ) and the doubly labelled water (DLW) method among male patients with stable/at risk for COPD. METHOD: In this cross-sectional observational study, data for 33 male patients were analysed. At the first visit, EI was estimated using a BDHQ (EIBDHQ). Total energy expenditure (TEE) was measured during 13-15 days by the DLW method, while corrected EI was calculated using the TEE and weight change during the DLW period (EIDLW). The difference between EIBDHQ and EIDLW was evaluated by the Bland-Altman method. Multiple regression analysis was used to determine the proportion of variance in the difference between EIBDHQ and EIDLW, as determined by the patient's characteristics. RESULTS: EIBDHQ was 2100 (95% CI: 1905 to 2295) kcal/day in the total population. A fixed bias was observed between EIBDHQ and EIDLW as -186 (95% CI: -422 to 50) kcal/day, while a proportional bias was not detected by the Bland-Altman analysis. Age, weight, anxiety and interleukin 6 were responsible for 61.7% of the variance in the difference between both EIs in a multiple regression model. CONCLUSIONS: The BDHQ underestimated EI among male patients with stable/at risk for COPD, but this estimation error was within an acceptable range compared with previous studies. EIBDHQ precision might be improved by considering common COPD traits, including inflammatory condition and mental state.

Energy expenditure and physical activity in COPD by doubly labelled water method and an accelerometer.

Although weight loss suggests poor prognosis of COPD, only a few studies have examined total energy expenditure (TEE) or physical activity level (PAL) using the doubly labelled water (DLW) method. We evaluated TEE and PAL using the DLW method together with a triaxial accelerometer to elucidate the relationships between TEE, PAL and clinical parameters leading to a practical means of monitoring COPD physical status. This study evaluated 50- to 79-year-old male patients with mild to very severe COPD (n=28) or at risk for COPD (n=8). TEE, activity energy expenditure for 2 weeks and basal metabolic rate were measured by DLW, an accelerometer and indirect calorimetry, respectively. All patients underwent pulmonary function, chest-computed tomography, 6-min walk test, body composition and grip strength tests. Relationships between indices of energy expenditure and clinical parameters were analysed. Bland-Altman analysis was used to examine the agreement of TEE and PAL between the DLW method and the accelerometer. TEE and PAL using DLW in the total population were 2273±445 kcal·day-1 and 1.80±0.20, respectively. TEE by DLW correlated well with that from the accelerometer and grip strength (p<0.0001), and PAL by DLW correlated well with that from the accelerometer (p<0.0001), grip strength and 6-min walk distance (p<0.001) among various clinical parameters. However, the accelerometer underestimated TEE (215±241 kcal·day-1) and PAL (0.18±0.16), with proportional biases in both indices. TEE and PAL can be estimated by accelerometer in patients with COPD if systematic errors and relevant clinical factors such as muscle strength and exercise capacity are accounted for.

Video-assisted thoracic surgery for a case of chronic progressive pulmonary aspergillosis undergoing haemodialysis complicated by anorexia nervosa: a case report.

We describe the case of a 37-year-old female with chronic progressive pulmonary aspergillosis (CPPA) with anorexia nervosa (AN) while undergoing haemodialysis for renal failure, who had video-assisted thoracic surgery (VATS) due to recurrent haemoptysis. She was referred to the Department of Respiratory Medicine for evaluation of an abnormal chest shadow. She was diagnosed with CPPA by serological examinations, radiological features, and bacterial culture. She was initially treated with oral antifungal therapy and transcatheter embolization. VATS lobectomy was eventually performed despite the AN and haemodialysis because of poorly controlled haemoptysis. The postoperative course was uneventful, and the final histopathological examination confirmed CPPA.

The product of trunk muscle area and density on the CT image is a good indicator of energy expenditure in patients with or at risk for COPD.

BACKGROUND: Physical inactivity due to cachexia and muscle wasting is well recognized as a sign of poor prognosis in chronic obstructive pulmonary disease (COPD). However, there have been no reports on the relationship between trunk muscle measurements and energy expenditure parameters, such as the total energy expenditure (TEE) and physical activity level (PAL), in COPD. In this study, we investigated the associations of computed tomography (CT)-derived muscle area and density measurements with clinical parameters, including TEE and PAL, in patients with or at risk for COPD, and examined whether these muscle measurements serve as an indicator of TEE and PAL. METHODS: The study population consisted of 36 male patients with (n = 28, stage 1-4) and at risk for (n = 8) COPD aged over 50 years. TEE was measured by the doubly labeled water method, and PAL was calculated as the TEE/basal metabolic rate estimated by the indirect method. The cross-sectional areas and densities of the pectoralis muscles, rectus abdominis muscles, and erector spinae muscles were measured. We evaluated the relationship between these muscle measurements and clinical outcomes, including body composition, lung function, muscle strength, TEE, and PAL. RESULTS: All the muscle areas were significantly associated with TEE, severity of emphysema, and body composition indices such as body mass index, fat-free mass, and trunk muscle mass. All trunk muscle densities were correlated with PAL. The product of the rectus abdominis muscle area and density showed the highest association with TEE (r = 0.732) and PAL (r = 0.578). Several trunk muscle measurements showed significant correlations with maximal inspiratory and expiratory pressures, indicating their roles in respiration. CONCLUSIONS: CT-derived measurements for trunk muscles are helpful in evaluating physical status and function in patients with or at risk for COPD. Particularly, trunk muscle evaluation may be a useful marker reflecting TEE and PAL.

Long-term Survival of a Patient with Small Cell Lung Cancer Secreting ADH and ACTH Simultaneously, Following the Prolonged Use of Amrubicin.

Paraneoplastic syndromes are frequently observed in lung cancer, especially in small cell lung cancer (SCLC). Although there have been many reports on paraneoplastic syndromes, few reports have been published on SCLC that simultaneously produces antidiuretic hormone (ADH) and adrenocorticotropic hormone (ACTH), and these reports described the prognosis of such cases as extremely poor. We herein present a rare case of a Japanese woman with SCLC accompanied by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Cushing's syndrome. The survival of the patient was prolonged by the long-term administration of amrubicin.

Pseudomesotheliomatous Carcinoma with a High Pleural Hyaluronic Acid Concentration Arising from a Primary Esophageal Squamous Cell Carcinoma.

BACKGROUND Pseudomesotheliomatous carcinomas are rare tumors that develop like malignant pleural mesothelioma (MPM). These tumors have similar features, and thus pseudomesotheliomatous carcinomas can sometimes be misdiagnosed as MPM. Most pseudomesotheliomatous carcinomas develop from primary lung cancers, although there have been some reports involving other malignancies; however, there has been no report describing a pseudomesotheliomatous carcinoma developing from an esophageal squamous cell carcinoma (ESCC). To the best of our knowledge, this is the first case report describing pseudomesotheliomatous carcinoma originating from primary ESCC. CASE REPORT A 65-year-old man was admitted to our hospital because of persistent cough and right chest pain. Radiological examination suggested MPM, and a high concentration of pleural hyaluronic acid was also observed. Cytological examination of pleural effusion confirmed metastatic squamous cell carcinoma, and ESCC was confirmed by upper-gastrointestinal endoscopy. The patient received cisplatin and 5-FU combination chemotherapy as first-line treatment, and docetaxel chemotherapy as second-line treatment. However, the patient's condition deteriorated, and he died 6 months after the diagnosis was established. We performed an autopsy and found that ESCC had invaded the lung, pleura, peritoneum, liver, stomach, ureter, bladder, spine, and lymph nodes. CONCLUSIONS We demonstrated that primary ESCC can give rise to a pseudomesotheliomatous carcinoma. This report describes the clinical features and outcome of such a patient, with an emphasis on differential diagnosis of MPM.

Plasma sE-cadherin and the plasma sE-cadherin/sVE-cadherin ratio are potential biomarkers for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with endothelial dysfunction. Cadherins are adhesion molecules on epithelial (E-) and vascular endothelial (VE-) cells. Soluble (s) cadherin is released from the cell surface by the effects of proteases including matrix metalloproteinases (MMPs). OBJECTIVE: The aim of this study was to examine the associations of sE-/sVE-cadherin levels in plasma with the development of COPD. METHODS: Plasma sE-/VE-cadherin levels were measured by an enzyme-linked immunosorbent assay in 115 patients with COPD, 36 symptomatic smokers (SS), 63 healthy smokers (HS) and 78 healthy non-smokers (HN). sE-cadherin and MMP-7 levels in epithelial lining fluid (ELF) were measured in 24 patients (12 COPD and 12 control). RESULTS: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios were significantly higher in COPD and SS than in HS and HN groups, while plasma sVE-cadherin levels were lower in COPD than in HS and HN groups (p < 0.0001). sE-cadherin levels paralleled the severity of airflow limitation in both plasma (p < 0.01) and ELF (p < 0.05), while plasma sVE-cadherin levels were inversely correlated with the extent of emphysema (p < 0.05). MMP-7 levels were correlated with sE-cadherin levels in ELF. CONCLUSIONS: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios are potential biomarkers for COPD.

Plasma Cathepsin S and Cathepsin S/Cystatin C Ratios Are Potential Biomarkers for COPD.

Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD. Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction ("at risk"; AR). In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses. Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p < 0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV1 predicted < 50%; p = 0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA ≥ 8.0; p = 0.001). Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD.

Plasma cytokine profiles related to smoking-sensitivity and phenotypes of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) develops only in smoking-sensitive smokers and manifests heterogeneous phenotypes, including emphysema and non-emphysema types. We aimed to identify biomarkers related to the smoking-sensitivity and phenotypes of COPD. Among 240 smokers suggestive of COPD, we studied on four groups defined by % forced expiratory volume in one second (FEV1) and computed tomography-based pulmonary emphysema. Plasma concentrations of 33 inflammatory markers were measured in four groups as well as Non-smokers using multiplex protein arrays. IL-5, IL-7 and IL-13 were identified to be associated with smoking sensitivity and IL-6 and IL-10 were candidate biomarkers for airway-lesion dominant COPD.

Analysis of comorbid factors that increase the COPD assessment test scores.

BACKGROUND: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores. METHODS: An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients' reports, physicians' records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed. RESULTS: The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients. CONCLUSIONS: Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized. TRIAL REGISTRATION: Clinical trial registered with UMIN (UMIN000003470).

[Appropriate hemodialysis scheduling based on therapeutic drug monitoring of carboplatin in a patient with lung cancer and chronic renal failure].

A 69-year-old woman undergoing hemodialysis due to ANCA-associated nephritis and chronic renal failure developed lung adenocarcinoma and underwent radical surgery. Upon recurrence of her cancer, she received combination chemotherapy with carboplatin (CBDCA) 150 mg/m2 and docetaxel 35-70 mg/m2. Concentration of free CBDCA in serum was monitored for 6 days after drug administration. Hemodialysis was performed 1 hour after administration of CBDCA, and on day 4. Despite the lower maximum concentration, serum CBDCA levels 20-24 h after chemotherapy in this patient were 15 to 20 times higher than in subjects with normal renal function who received CBDCA at the area under the curve (AUC) of 5. She experienced moderate to severe nausea and vomiting which persisted for 12 days. During her second course of chemotherapy, hemodialysis was performed for 3 consecutive days after drug administration. The serum CBDCA levels on day 2 or later remained lower than in the first course, and the patient experienced fewer severe side effects. Based on the data from therapeutic drug monitoring of CBDCA, hemodialysis for 3 consecutive days after drug administration has been demonstrated to be useful for treatment of a patient with chronic renal failure receiving chemotherapy with CBDCA.

Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice.

Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS- group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS- group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS-) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS- group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS- group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.