Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer.

PURPOSE: Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors. METHODS: Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined. RESULTS: Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale. CONCLUSION: Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

Short-term intermittent cigarette smoke exposure enhances alveolar type 2 cell stemness via fatty acid oxidation.

BACKGROUND: Cigarette smoke (CS) is associated with chronic obstructive pulmonary disease (COPD) and cancer. However, the underlying pathological mechanisms are not well understood. We recently reported that mice exposed to long-term intermittent CS for 3 months developed more severe emphysema and higher incidence of adenocarcinoma than mice exposed to long-term continuous CS for 3 months and long-term continuous CS exposure activated alveolar stem cell proliferation. However, the influence of variations in the CS exposure pattern in alveolar stem cell in unknown. Here, we exposed mice to 3 weeks of continuous or intermittent CS to identify whether different CS exposure patterns would result in differential effects on stem cells and the mechanisms underlying these potential differences. METHODS: Female mice expressing GFP in alveolar type 2 (AT2) cells, which are stem cells of the alveolar compartment, were exposed to mainstream CS via nasal inhalation. AT2 cells were collected based on their GFP expression by flow cytometry and co-cultured with fibroblasts in stem cell 3D organoid/colony-forming assays. We compared gene expression profiles of continuous and intermittent CS-exposed AT2 cells using microarray analysis and performed a functional assessment of a differentially expressed gene to confirm its involvement in the process using activator and inhibitor studies. RESULTS: AT2 cells sorted from intermittent CS-exposed mice formed significantly more colonies compared to those from continuous CS-exposed mice, and both CS-exposed groups formed significantly more colonies when compared to air-exposed cells. Comparative microarray analysis revealed the upregulation of genes related to fatty acid oxidation (FAO) pathways in AT2 cells from intermittent CS-exposed mice. Treatment of intermittent CS-exposed mice with etomoxir, an inhibitor of the FAO regulator Cpt1a, for 5 weeks resulted in a significant suppression of the efficiency of AT2 cell colony formation. In vitro treatment of naïve AT2 cells with a FAO activator and inhibitor further confirmed the relationship between FAO and AT2 stem cell function. CONCLUSIONS: Alveolar stem cell function was more strongly activated by intermittent CS exposure than by continuous CS exposure. We provide evidence that AT2 stem cells respond to intermittent CS exposure by activating stem cell proliferation via the activation of FAO.

Serum soluble interleukin-2 receptor level is a predictive marker for EBUS-TBNA-based diagnosis of sarcoidosis.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widely available diagnostic tool for suspected stage I/II sarcoidosis. Combination of EBUS-TBNA and transbronchial lung biopsy (TBLB) has been proposed as diagnostic procedure in clinical settings. OBJECTIVES: The aim of this study was to assess the diagnostic yield of combined EBUS-TBNA and TBLB and identify the markers correlated with a high diagnostic rate. METHODS: We retrospectively analyzed the data of 37 patients with suspected stage I/II sarcoidosis with enlarged hilar or mediastinal lymph nodes on computed tomography (CT) images. These patients had been scheduled to undergo EBUS-TBNA and TBLB. Serum levels of sarcoidosis markers (angiotensin-converting enzyme [ACE], soluble interleukin-2 receptor [sIL-2R], and lysozyme), CT findings, and examination techniques were evaluated as predictive markers for diagnosis. RESULTS: Of the 37 patients, 32 had undergone both EBUS-TBNA and TBLB, while the remaining 5 patients had only undergone EBUS-TBNA. The diagnosis was confirmed by TBLB in 16 of the 32 patients (50.0%), EBUS-TBNA in 31 of the 37 patients (83.8%), and combined TBLB and EBUS-TBNA in all patients (100.0%). The serum level of sIL-2R, but not that of ACE or lysozyme, was correlated with successful diagnosis by EBUS-TBNA. CONCLUSION: In patients with stage I/II sarcoidosis, the serum level of sIL-2R is a promising and useful marker for predicting the diagnosis by EBUS-TBNA and reducing the burden of additional TBLB and its possible complications. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 8-16).

Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells.

Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP+/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)-dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma-like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF-secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell-recruiting cytokines. CAFs also enhanced the conversion of tumour-associated macrophages (TAMs) to the tumour-supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr-independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9-induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Predictive and modifying factors of bone mineral density decline in patients with COPD.

RATIONALE: Various determinants of osteoporosis have been previously identified. However, only a few longitudinal studies have examined related factors. We aimed to investigate factors predicting and modifying rapid decline of bone mineral density in patients with chronic obstructive pulmonary disease. METHODS: We analyzed patients with chronic obstructive pulmonary disease whose bone mineral density were measured at least three times over three years (n = 111). We divided annual per cent changes of bone mineral density in different body parts into tertiles. Rapid decliners (n = 33) were defined as those with the largest decline in at least two parts; all other participants were defined as non-rapid decliners (n = 78). RESULTS: At enrollment, bone mineral density did not differ between the two groups. However, rapid decliners had a significantly greater rate of new vertebral fractures over 3 years compared with non-rapid decliners. On multivariate logistic regression analysis, age, moderate to severe emphysema, no daily exercise habits, and anemia increased the likelihood of rapid decliners. Furthermore, patients who newly started and continued bisphosphonate exhibited higher annual per cent changes of bone mineral density than did those without bisphosphonate use. CONCLUSIONS: A rapid decline in bone mineral density correlates to a higher likelihood of vertebral fracture. We clarified the predictors of bone mineral density decline and demonstrated that bisphosphonate use might modify bone mineral density in patients with chronic obstructive pulmonary disease.

Impact of a Novel Smartphone App (CureApp Smoking Cessation) on Nicotine Dependence: Prospective Single-Arm Interventional Pilot Study.

BACKGROUND: Mobile apps have been considered to provide active and continuous support for smoking cessation. However, it is yet to be known whether a smoking cessation smartphone app improves long-term abstinence rates in nicotine-dependent patients. OBJECTIVE: This study aimed to evaluate the long-term abstinence effect of a novel smartphone app, CureApp Smoking Cessation (CASC), in patients with nicotine dependence. METHODS: In this prospective, interventional, multicenter, single-arm study, we provided the CASC app to all the participants, who used it daily for 24 weeks. The CASC app includes features to maximize the therapeutic effect of pharmacological therapies and counseling at outpatient clinics for smoking cessation. The primary endpoint was a continuous abstinence rate (CAR) from weeks 9 to 24, whereas secondary endpoints were CARs from weeks 9 to 12 and 9 to 52. RESULTS: Of the 56 adult smokers recruited, 1 did not download the app; therefore, 55 participants constituted the full analysis sample. The CAR from weeks 9 to 24 was 64% (35/55, 95% CI 51%-76%), whereas the CARs from weeks 9 to 12 and 9 to 52 were 76% (42/55, 95% CI 65%-88%) and 58% (32/55, 95% CI 46%-71%), respectively. These CARs were better than the results of the national survey on outpatient clinics with regard to smoking cessation under the National Health Insurance Program and that of the varenicline phase 3 trial in Japan and the United States. There was only 1 participant who dropped out during the 12 weeks of the treatment period. This treatment decreased the scores related to withdrawal and craving symptoms. CONCLUSIONS: The addition of CASC to usual smoking cessation therapies resulted in high CARs, high patient retention rates, and improvement of cessation-related symptoms. The smartphone app CASC is a feasible and useful tool to help long-term continuous abstinence that can be combined with a standard smoking cessation treatment program.

Clinical utility of blood neutrophil-lymphocyte ratio in Japanese COPD patients.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of inflammation in chronic obstructive pulmonary disease (COPD) patients. But, a meaningful threshold and the longitudinal changes are unknown. We aimed to investigate the association between NLR and the clinical characteristics of COPD patients and to determine a meaningful threshold and the longitudinal changes for NLR. METHODS: Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. We performed a blood examination and a pulmonary function test. Blood examination was completed at baseline and annually thereafter, at a time when the disease was stable. Two hundred seventy-four patients who had at least 3 blood examinations over 3 years were included. RESULTS: Baseline NLR was correlated with baseline C-reactive protein (CRP) (r = 0.18, p = 0.003) and SAA (r = 0.34, p <  0.001). We defined an NLR score of 2.7 as the arbitrary cut-off value based on upper quartile points. COPD patients with NLR ≥ 2.7 were older (p = 0.037), had a lower BMI (p = 0.005) and a lower %FEV1 (p = 0.0003) compared to patients with NLR < 2.7. Receiver-operating-characteristic (ROC) curves showed the optimal cutoff for the baseline NLR in the predicting moderate/severe exacerbation to be 2.7, which was same as the upper quartile points. Follow-up analysis over 3 years revealed that the differences in the trends of NLR among the three groups based on the categories of exacerbations (moderate or severe, mild, no exacerbation) were significant (p = 0.006). CONCLUSIONS: NLR is associated with COPD severity and exacerbations. For predicting exacerbations, we estimated the threshold of NLR to be 2.7 at baseline. TRIAL REGISTRATION: Clinical trial registered with the University Hospital Medication Information Network ( UMIN000003470 , April 10, 2010).

Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More than Continuous Exposure.

Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)-induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.

Effects of long-term cigarette smoke exposure on bone metabolism, structure, and quality in a mouse model of emphysema.

Smoking is a common risk factor for both chronic obstructive pulmonary disease (COPD) and osteoporosis. In patients with COPD, severe emphysema is a risk factor for vertebral fracture; however, the effects of smoking or emphysema on bone health remain largely unknown. We report bone deterioration in a mouse model of emphysema induced by nose-only cigarette smoke (CS) exposure. Unexpectedly, short-term exposure for 4-weeks decreased bone turnover and increased bone volume in mice. However, prolonged exposure for 20- and 40-weeks reversed the effects from suppression to promotion of bone resorption. This long-term CS exposure increased osteoclast number and impaired bone growth, while it increased bone volume. Strikingly, long-term CS exposure deteriorated bone quality of the lumbar vertebrae as illustrated by disorientation of collagen fibers and the biological apatite c-axis. This animal model may provide a better understanding of the mechanisms underlying the deterioration of bone quality in pulmonary emphysema caused by smoking.

Impact of cataract on health-related quality of life in a longitudinal Japanese chronic obstructive pulmonary cohort.

Cigarette smoking increases the risk of developing both cataract and chronic obstructive pulmonary disease (COPD). The prevalence of cataract and the clinical characteristics of COPD patients with cataract were retrospectively investigated in a 2-year observational COPD cohort. We analyzed 395 patients with complete data on ophthalmologic evaluation (319 subjects with COPD and 76 subjects at risk of COPD). There was no difference in the prevalence of cataract between COPD patients and those at risk (47.0% vs. 42.1%, p = 0.44). Age ≥ 75 years, low body mass index, and hypertension were independently associated with cataract as a comorbidity in COPD. The incidence of exacerbation within 2 years was significantly higher in COPD patients with cataract than those without cataract (36.6% vs. 18.3%, p = 0.0019). COPD patients with cataract exhibited significantly higher COPD assessment test score compared to those without cataract (13.7 ± 8.9 vs. 11.5 ± 7.2, p = 0.0240). Overall St George's Respiratory Questionnaire score and each component were significantly worse in COPD patients with cataract compared to those without cataract. COPD patients with cataract exhibited poor health-related quality of life and frequent exacerbations. The association between cataract and exacerbations of COPD deserves further attention.

Relationship between diminution of small pulmonary vessels and emphysema in chronic obstructive pulmonary disease.

OBJECTIVES: To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD). METHODS: Forty-nine patients were included. The percentage of cross-sectional area of vessels <5mm2 (%CSA <5) and extent of emphysema were assessed. RESULTS: Less than half of the COPD patients demonstrated an inverse correlation between %CSA <5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA <5 was homogeneously distributed. CONCLUSION: Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA <5 and LAA% in individual lungs.

Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease.

BACKGROUND: Only a few studies have evaluated the radiologic features of pre-existing structural abnormalities where lung cancer may develop. This study aimed to analyze the computed tomography (CT) images of lung areas where new cancer developed in chronic obstructive pulmonary disease (COPD) patients. PATIENTS AND METHODS: We conducted a multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research, to assess the incidence of lung cancer. Emphysema and interstitial abnormalities were evaluated in 240 COPD patients who had baseline CT scans applicable for further digital analyses. For patients who developed lung cancer during the 3-year follow-up period, the local spherical lung density of the precancerous area was individually quantified. RESULTS: Lung cancer was newly diagnosed in 21 participants (2.3% per year). The percent-age of low attenuation area in patients who developed lung cancer was higher than that of the other patients (20.0% vs 10.4%, P=0.014). The presence of emphysema (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0-29.0, P=0.049) or interstitial lung abnormalities (OR 15.6, 95% CI 4.4-65.4, P<0.0001) independently increased the risk for lung cancer. Compared with the density of the entire lung, the local density of the precancerous area was almost the same in patients with heterogeneous emphysema, but it was higher in most patients with interstitial abnormalities. CONCLUSION: The presence of emphysema or interstitial abnormalities or a combination of both were independent predictors of lung cancer development in COPD patients. Furthermore, lung cancer most often developed in non-emphysematous areas or in interstitial abnormalities.

Identification of five clusters of comorbidities in a longitudinal Japanese chronic obstructive pulmonary disease cohort.

BACKGROUND AND OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. MATERIAL AND METHODS: The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. RESULTS: Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (DLco/VA) compared to the malignancy cluster (p = 0.036). CONCLUSIONS: Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years.

Impact of mild exacerbation on COPD symptoms in a Japanese cohort.

BACKGROUND: Patients with COPD might not report mild exacerbation. The frequency, risk factors, and impact of mild exacerbation on COPD status are unknown. OBJECTIVES: The present study was performed to compare features between mild exacerbation and moderate or severe exacerbation in Japanese patients with COPD. PATIENTS AND METHODS: An observational COPD cohort was designed at Keio University and affiliated hospitals to prospectively investigate the management of COPD comorbidities. This study analyzes data only from patients with COPD who had completed annual examinations and questionnaires over a period of 2 years (n=311). RESULTS: Among 59 patients with mild exacerbations during the first year, 32.2% also experienced only mild exacerbations in the second year. Among 60 patients with moderate or severe exacerbations during the first year, 40% also had the same severity of exacerbation during the second year. Findings of the COPD assessment test and the symptom component of the St George's Respiratory Questionnaire at steady state were worse in patients with mild exacerbations than in those who were exacerbation free during the 2-year study period, although the severity of the ratio of predicted forced expiratory volume in 1 second did not differ between them. Severe airflow limitation (the ratio of predicted forced expiratory volume in 1 second <50%) and experience of mild exacerbations independently advanced the likelihood of an elevated COPD assessment test score to ≥2 per year. CONCLUSION: The severity of COPD exacerbation seemed to be temporally stable over 2 years, and even mild exacerbations adversely impacted the health-related quality of life of patients with COPD.

Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer.

Lung cancer is the most lethal cancer in the world. Intensive research is ongoing worldwide to identify new therapies for lung cancer. Several mouse models of lung cancer are being used to study the mechanism of cancer development and to experiment with various therapeutic strategies. However, the absence of a real-time technique to identify the development of tumor nodules in mice lungs and to monitor the changes in their size in response to various experimental and therapeutic interventions hampers the ability to obtain an accurate description of the course of the disease and its timely response to treatments. In this study, a method using a micro-computed tomography (CT) scanner for the detection of the development of lung tumors in a mouse model of lung adenocarcinoma is described. Next, we show that monthly follow-up with micro-CT can identify dynamic changes in the lung tumor, such as the appearance of additional nodules, increase in the size of previously detected nodules, and decrease in the size or complete resolution of nodules in response to treatment. Finally, the accuracy of this real-time assessment method was confirmed with end-point histological quantification. This technique paves the way for planning and conducting more complex experiments on lung cancer animal models, and it enables us to better understand the mechanisms of carcinogenesis and the effects of different treatment modalities while saving time and resources.

Multiple nodular lesions following Pneumocystis pneumonia in a non-HIV immunocompromised patient.

Cytomegalovirus superinfection is associated with a poor prognosis in non-HIV Pneumocystis pneumonia (PCP) and can cause deterioration of PCP not only simultaneously but also after initiating PCP treatment. Cytomegalovirus pneumonia should be considered in cases with deterioration after initiating PCP treatment; multiple nodular lesions are useful findings for the diagnosis.

Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD)--typically caused by bacterial or viral infection--is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. METHODS: We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. RESULTS: In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. CONCLUSIONS: These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro-computed tomography.

Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End-expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS-exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice.