Validity and reliability of the Korean version of the Wisconsin Smoking Withdrawal Scale.

BACKGROUND/AIMS: This study evaluated the validity and reliability of the Korean version of the Wisconsin Smoking Withdrawal Scale (WSWS-K) for use in clinical practice and research on Korean smokers. METHODS: The Wisconsin Smoking Withdrawal Scale was translated into Korean and then back-translated into English. The authors reviewed the translation and back-translation and approved the final questionnaire draft. The validity and reliability of the WSWS-K were evaluated based on data collected from 300 participants. Construct validity was evaluated with a confirmatory factor analysis. Criterion-related validity was assessed by examining the relationships between the subscales of the WSWS-K and the matched items of the Korean version of the Minnesota Nicotine Withdrawal Scale (MNWS-K). RESULTS: The participants were predominantly male (93.6%) and the mean age was 59.23 ± 15.19 years. The confirmatory factor analysis revealed that fit indices (namely, the goodness-of-fit index, adjusted goodness-of-fit index, comparative fit index, and the normed fit index) exceeded or approached 0.9. Cronbach's alpha for the entire scale was 0.87. The total score of the WSWS-K had a statistically significant positive correlation with that of the MNWS-K (Pearson's correlation coefficient, 0.768; p < 0.01). Additionally, we performed linear regression between the WSWS-K and MNWS-K scores after adjusting for age, gender, comorbidity, and smoking history. After this adjustment, the p value of the WSWS- K was < 0.001. CONCLUSION: The WSWS-K had satisfactory validity and reliability. The WSWS- K can be used with acceptable validity and reliability in research and clinical evaluation of Korean smokers.

Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer.

BACKGROUND/AIMS: We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice. METHODS: Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated. RESULTS: Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8-hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy. CONCLUSIONS: Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

Factors Related to the Diagnostic Yield of Flexible Bronchoscopy without Guidance in Bronchoscopically Invisible Peripheral Lung Lesions.

BACKGROUND: We aimed to analyze the factors predicting the diagnostic performance of flexible bronchoscopy without guidance in peripheral lung lesions that are endoscopically invisible. METHODS: This was a retrospective study conducted in St. Paul's Hospital, The Catholic University of Korea, between January 2007 and March 2013. We included all patients who received bronchoscopy during this period. The analyzed variables were age, sex, the etiology of the lesion, lesion size, distance from the pleura, and presence of the bronchus sign. We used multiple logistic regression analysis to identify the significant independent factors associated with diagnostic yield. RESULTS: We included 151 patients in this study. The overall diagnostic yield was 58.3%. The sensitivity was 43.2% for malignant disease and 78.1% for benign disease. The benign lung lesions (p<0.001), lesion size (p=0.015), presence of the exposed type of bronchus sign (p<0.001), and presence of cavitary lung lesions (p=0.005) were factors influencing the yield of flexible bronchoscopy by univariate analysis. In a multivariate logistic regression analysis, the exposed type of bronchus sign and benign lung lesions were independent predicting factors (odds ratio [OR]: 27.95; 95% confidence interval [CI], 7.56-103.32; p<0.001 and OR, 4.91; 95% CI, 1.76-13.72; p=0.002). CONCLUSION: The presence of the exposed type of bronchus sign and benign lung lesions are determining factors of the diagnostic yield in flexible bronchoscopy in evaluating peripheral lesions that are not endoscopically visible.

Dyspnea as a Prognostic Factor in Patients with Non-Small Cell Lung Cancer.

PURPOSE: To investigate associations between dyspnea and clinical outcomes in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: From 2001 to 2014, we retrospectively reviewed the prospective lung cancer database of St. Paul's Hospital at the Catholic University of Korea. We enrolled patients with NSCLC and evaluated symptoms of dyspnea using modified Medical Research Council (mMRC) scores. Also, we estimated pulmonary functions and analyzed survival data. RESULTS: In total, 457 NSCLC patients were enrolled, and 259 (56.7%) had dyspnea. Among those with dyspnea and whose mMRC scores were available (109 patients had no mMRC score), 85 (56.6%) patients had an mMRC score <2, while 65 (43.3%) had an mMRC score ≥2. Significant decreased pulmonary functions were observed in patients with dyspnea. In multivariate analysis, aging, poor performance status, advanced stage, low forced expiratory volume in 1 second (%), and an mMRC score ≥2 were found to be significant prognostic factors for patient survival. CONCLUSION: Dyspnea could be a significant prognostic factor in patients with NSCLC.

The apoptotic effect of simvastatin via the upregulation of BIM in nonsmall cell lung cancer cells.

PURPOSE: Statins are known to have pleiotropic effects that induce cell death in certain cancer cells. BIM is a member of the bcl-2 gene family, which promotes apoptotic cell death. This study investigated the hypothesis that simvastatin has pro-apoptotic effects in epidermal growth factor receptor (EGFR)-mutated lung cancer cell lines via the upregulation of the expression of the BIM protein. MATERIALS AND METHODS: The cytotoxic effects of simvastatin on gefitinib-sensitive (HCC827, E716-A750del) and -resistant (H1975, T790M + L858R) nonsmall cell lung cancer (NSCLC) cells were compared. Cell proliferation and expression of apoptosis-related and EGFR downstream signaling proteins were evaluated. Expression of BIM was compared in H1975 cells after treatment with simvastatin or gefitinib. SiRNA-mediated BIM depletion was performed to confirm whether the cytotoxicity of simvastatin was mediated by the expression of BIM. RESULTS: H1975 cells showed significantly reduced viability compared with HCC827 cells after treatment with simvastatin (2 µM) for 48 hours. In simvastatin-treated H1975 cells, expression of pro-apoptotic proteins was increased and the phosphorylation of ERK 1/2 (p-ERK 1/2) was reduced. Expression of BIM was suppressed by gefitinib (1 µM) treatment in H1975 cells, but it was significantly increased by treatment with simvastatin. BIM depletion by siRNA transfection enhanced the viability of H1975 cells that received simvastatin treatment and increased their expression of anti-apoptotic proteins. CONCLUSIONS: Simvastatin restored the expression of BIM to induce apoptotic cell death in NSCLC cells harboring an EGFR-resistant mutation. Our study suggests the potential utility of simvastatin as a BIM-targeted treatment for NSCLC.

Serious Complications after Self-expandable Metallic Stent Insertion in a Patient with Malignant Lymphoma.

An 18-year-old woman was evaluated for a chronic productive cough and dyspnea. She was subsequently diagnosed with mediastinal non-Hodgkin lymphoma (NHL). A covered self-expandable metallic stent (SEMS) was implanted to relieve narrowing in for both main bronchi. The NHL went into complete remission after six chemotherapy cycles, but atelectasis developed in the left lower lobe 18 months after SEMS insertion. The left main bronchus was completely occluded by granulation tissue. However, the right main bronchus and intermedius bronchus were patent. Granulation tissue was observed adjacent to the SEMS. The granulation tissue and the SEMS were excised, and a silicone stent was successfully implanted using a rigid bronchoscope. SEMS is advantageous owing to its easy implantation, but there are considerable potential complications such as severe reactive granulation, stent rupture, and ventilation failure in serious cases. Therefore, SEMS should be avoided whenever possible in patients with benign airway disease. This case highlights that SEMS implantation should be avoided even in malignant airway obstruction cases if the underlying malignancy is curable.

Curcumin sensitizes human lung cancer cells to apoptosis and metastasis synergistically combined with carboplatin.

Although carboplatin is one of the standard chemotherapeutic agents for non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance. Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether curcumin can chemosensitize lung cancer cells to carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of curcumin and carboplatin alone and in combination. Combined treatment with curcumin and carboplatin inhibited tumor cell growth, migration, and invasion compared with either drug alone. Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone. mRNA and protein expression of caspase-3 and caspase-9 and proapoptotic genes was increased in cells treated with a combination of curcumin and carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of curcumin combined with carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism, curcumin has potential as a chemosensitizer for carboplatin in the treatment of patients with NSCLC.

Efficacy of team-based financial incentives for smoking cessation in the workplace.

Worksite smoking cessation programs offer accessibility of the target population, availability of occupational health support, and the potential for peer pressure and peer support. The purpose of this study was to identify the efficacy of the financial incentives given to various teams in the workplace. St. Paul's Hospital's employees were enrolled. Each team of employees consisted of smoking participants and non-smoking fellow workers from the same department. The financial incentive of 50000 won (about $45) was rewarded to the team for each successful participant-not to individual members-after the first week and then after one month. If the smokers in the team remained abstinent for a longer time period, the team was given an incentive of 100000 won for each successful participant after 3 and 6 months. A total 28 smoking participants and 6 teams were enrolled. Self-reported abstinence rates validated by urinary cotinine test at 3, 6, and 12 months after the initial cessation were 61%, 54%, and 50%, respectively. Smokers with high nicotine dependence scores or those who began participation 1 month after enrollment initiation had a lower abstinence rate at 3 months, but not at 6 and 12 months. Participants who succeeded at smoking cessation at 12 months were more likely to be older and have a longer smoking duration history. The financial incentives given to teams could be promising and effective to improve long-term rates of smoking cessation. This approach could use peer pressure and peer support in the workplace over a longer period.

The associations between anthropometric indices and obstructive sleep apnea in a Korean population.

BACKGROUND: Obesity is a major risk factor for the development of obstructive sleep apnea (OSA). Although clinical and epidemiological studies have shown that OSA and obesity are strongly associated, few Asian studies have examined the associations between anthropometric obesity indices and OSA, especially in the Korean population. The purpose of this study was to evaluate the influence of anthropometric obesity indices on OSA in a Korean population. METHODS: Anthropometric indices, including neck circumference, waist circumference, and body mass index, were assessed in 383 consecutive subjects with suspected OSA. RESULTS: Of the 383 subjects assessed, 316 (82.5%) were diagnosed with OSA. Neck circumference (r = 0.518), waist circumference (r = 0.570), and body mass index (r = 0.512) were correlated with the apnea-hypopnea index (p<0.001, for all). After adjusting for age, sex, alcohol consumption, and smoking, a logistic regression model showed that neck circumference [odds ratio (OR), 1.414; p<0.001)], waist circumference (OR, 1.114; p<0.001), and body mass index (OR, 1.364; p<0.001) were associated with OSA. The linear regression model showed that neck circumference (ß = 3.748, p<0.001), waist circumference (ß = 1.272, p<0.001), and body mass index (ß = 3.082, p<0.001) were associated with apnea-hypopnea index. The cut-off values for predicting OSA were determined as 34.5 cm for neck circumference, 76.5 cm for waist circumference, and 23.05 kg/m2 for body mass index for females, and 38.75 cm for neck circumference, 88.5 cm for waist circumference, and 24.95 kg/m2 for body mass index for males. CONCLUSION: Increased anthropometric indices were significantly associated with the presence and severity of OSA in a Korean population. In addition, this study demonstrated the cut-off values for body mass index, waist circumference, and neck circumference for increased OSA risk.

A case of pneumomediastinum and parapneumonic effusions following pharyngeal perforation caused by shouting.

Spontaneous pneumomediastinum is an uncommon disorder, and usually affects young men and has a benign course. Common triggers are asthma, the smoking of illicit drugs, the Valsalva maneuver, and respiratory infections. Most cases are usually due to alveolar rupture into the pulmonary interstitium caused by excess pressure. The air dissects to the hilum along the peribronchovascular sheaths and spreads into the mediastinum. However, pneumomediastinum following pharyngeal perforation is very rare, and has only been reported in relation to dental procedures, head and neck surgery, or trauma. We report a case of pneumomediastinum that developed in a 43-year-old patient with pharyngeal perforation after shouting. His course was complicated by mediastinitis and parapneumonic effusions.

A multicenter phase II study of belotecan, a new camptothecin analogue, in elderly patients with previously untreated, extensive-stage small cell lung cancer.

PURPOSE: Belotecan is a new camptothecin analogue and a potent topoisomerase I inhibitor. The aim of this phase II study was to investigate the efficacy and toxicity of belotecan in previously untreated elderly patients with small cell lung cancer (SCLC). METHODS: A total of 26 patients, aged ≥65 years, with previously untreated, extensive-stage SCLC were enrolled in the study. Belotecan was administered by daily intravenous infusion at 0.5 mg/m(2)/day for 5 consecutive days every 3 weeks. RESULTS: The overall response rate and disease control rate of chemotherapy on an intention-to-treat basis were 35 and 54 %, respectively. The median overall survival was 6.4 months, and the median time to progression was 2.8 months. The most common toxicity was hematologic. Grade 3 or 4 neutropenia occurred in 80.8 % of patients, and grade 3 or 4 thrombocytopenia in 15.3 %. Non-hematologic toxic effects of grade 3 or 4 were uncommon. CONCLUSION: Belotecan had modest efficacy and well-tolerated toxicity in previously untreated, elderly SCLC patients. Single belotecan could be a promising treatment option, considering its lower toxicity in elderly patients who are unsuitable candidates for platinum plus etoposide chemotherapy.

A case of typhlitis developed after chemotherapy with irinotecan and Cisplatin in a patient with small cell lung carcinoma.

Typhlitis is a necrotizing colitis that usually occurs in neutropenic patients and develops most often in patients with hematologic malignancies such as leukemia and lymphoma. Typhlitis may proceed to bowel perforation, peritonitis and sepsis, which requires immediate treatment. Irinotecan is a semisynthetic analogue of the natural alkaloid camptothecin which prevents DNA from unwinding by inhibition of topoisomerase I. It is mainly used in colon cancer and small cell lung carcinoma (SCLC), of which the most common adverse effects are gastrointestinal toxicities. To the best of our knowledge, no case of typhlitis after chemotherapy with a standard dose of irinotecan in a solid tumor has been reported in the literature. We, herein, report the first case of typhlitis developed after chemotherapy combining irinotecan and cisplatin in a patient with SCLC.

Clinical experience of rigid bronchoscopy in single center.

BACKGROUND: The aim of this study was to analyze clinical situations requiring rigid bronchoscopy and evaluate usefulness of rigid bronchoscopic intervention in benign or malignant airway disorders. METHODS: We retrospectively reviewed 29 patients who underwent rigid bronchoscopy from November 2007 to February 2011 at St. Paul's Hospital, The Catholic University of Korea School of Medicine. RESULTS: Of the 29 patients, the most frequent underlying etiology was benign stenosis of trachea (n=20). Of those 20 patients, 16 had post-intubation tracheal stenosis (PITS), 2 had tracheal stenosis due to inhalation burn (IBTS) and other 2 had obstructive fibrinous tracheal pseudomembrane (OFTP). Other etiologies were airway malignancy (n=6), endobronchial stenosis due to tuberculosis (n=2), and foreign body (n=1). For treatment, silicone stent insertion was done in 16 cases of PITS and IBTS and mechanical removal was performed in 2 cases of OFTP. In 6 cases of malignant airway obstruction mechanical debulking was performed and silicone stents were inserted additionally in 2 cases. Balloon dilatation and electrocautery were used in 2 cases of endobronchial stenosis due to tuberculosis. In all cases of stent, airway obstructive symptom improved immediately. Granulation tissue formation was the most common complication. CONCLUSION: Tracheal stenosis was most common indication and silicone stenting was most common procedure of rigid bronchoscopy in our center. Rigid bronchoscopic procedures, at least tracheal silicone stenting, should be included in pulmonary medicine fellowship programs because it is a very effective and indispensable method to relieve critical airway obstruction which needs training to learn.

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-ß-induced alveolar epithelial to mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a lethal parenchymal lung disease characterized by myofibroblast proliferation. Alveolar epithelial cells (AECs) are thought to produce myofibroblasts through the epithelial to mesenchymal transition (EMT). Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis. RAGE is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products (AGE) with RAGE during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the TGF-ß-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by RAGE siRNA treatment. Thus, the induction of Smad7 by the AGE-RAGE interaction limits the development of pulmonary fibrosis by inhibiting TGF-ß-dependent signaling in AECs.

A multicenter phase II study of belotecan, a new camptothecin analogue, as a second-line therapy in patients with small cell lung cancer.

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan as a second-line therapy in patients with small cell lung cancer (SCLC). Patients who were previously treated for SCLC were entered into the study. Belotecan was given by daily intravenous infusion for five consecutive days, every three weeks. Twenty-five patients were enrolled in this study. On an intention-to-treat basis, belotecan induced an overall response rate of 24%, a median overall survival of 9.9 months, a median time to progression of 2.2 months, and a 1-year survival rate of 38.3%. Grade 3/4 neutropenia developed in 88.0% of patients and grade 3/4 thrombocytopenia in 40.0%. Nonhematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerated as a second-line agent in patients with SCLC.

Obstructive fibrinous tracheal pseudomembrane after tracheal intubation: a case report.

Obstructive fibrinous tracheal pseudomembrane is a rare, but potentially fatal complication associated with endotracheal intubation. It has been known that the formation of tracheal pseudomembrane is related with intracuff pressure during endotracheal intubation or infectious cause. But in the patient described in this case, pseudomembrane formation in the trachea was associated with subglottic epithelial trauma or caustic injuries to the trachea caused by aspirated gastric contents during intubation rather than tracheal ischemia due to high cuff pressure. We report a patient with obstructive fibrinous tracheal pseudomembrane after endotracheal intubation who presented with dyspnea and stridor and was treated successfully with mechanical removal using rigid bronchoscopy.

Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis.

CXC chemokine receptor 4 (CXCR4), which binds the stromal cell-derived factor-1 (SDF-1), has been shown to play a critical role in mobilizing the bone marrow (BM)-derived stem cells and inflammatory cells. We studied the effects of AMD3100, CXCR4 antagonist, on a murine bleomycin-induced pulmonary fibrosis model. Treatment of mice with AMD3100 in bleomycin-treated mice resulted in the decrease of SDF-1 in bronchoalveolar lavage (BAL) fluids at an early stage and was followed by the decrease of fibrocytes in the lung. AMD3100 treatment decreased the SDF-1 mRNA expression, fibrocyte numbers in the lung at an early stage (day 3) and CXCR4 expression at the later stage (day 7 and 21) after bleomycin injury. The collagen content and pulmonary fibrosis were significantly attenuated by AMD3100 treatment in later stage of bleomycin injury. AMD3100 treatment also decreased the murine mesenchymal and hematopoietic stem cell chemotaxis when either in the stimulation with bleomycin treated lung lysates or SDF-1 in vitro. In BM stem cell experiments, the phosphorylation of p38 MAPK which was induced by SDF-1 was significantly blocked by addition of AMD3100. Our data suggest that AMD3100 might be effective in preventing the pulmonary fibrosis by inhibiting the fibrocyte mobilization to the injured lung via blocking the SDF-1/CXCR4 axis.

Diagnostic yield of flexible bronchoscopy without fluoroscopic guidance in evaluating peripheral lung lesions.

BACKGROUND AND OBJECTIVES: Flexible bronchoscopy (FB) is frequently performed in patients with peripheral lung lesions. The aim of this study was to evaluate the diagnostic yield, factors affecting diagnostic yield, complications, and safety of FB without fluoroscopic guidance in patients with peripheral lung lesions. METHODS: We retrospectively reviewed the medical records of all patients who underwent FB without fluoroscopic guidance for the diagnosis of peripheral lung lesions between 1999 and 2004. RESULTS: Ninety-three patients were enrolled. Among these, 38 lesions were malignant, 46 were benign, and 9 were indeterminate. The overall diagnostic rate was 65%, and the diagnostic sensitivities for malignant and benign lesions were 68% and 74%, respectively. The diagnostic yield was significantly higher for lesions >2 cm (70%) than for lesions ≤2 cm (11%; P <0.001). The diagnostic yield of transbronchial lung biopsy (46%) was higher than that of bronchial washing (29%; P=0.025) or brushing (29%; P=0.022). The yield of transbronchial lung biopsy for malignant disease (70%) was higher than that of benign disease (35%; P=0.003). Pneumothoraces and significant bleeding developed in 4.3% and 2.2% of patients, respectively. CONCLUSIONS: This study showed that FB sampling without fluoroscopic guidance was safe with a high rate of accuracy for the diagnosis of lung lesions not visible through a bronchoscope. When we performed a computed tomography scan and determined the exact location of the lesion before FB, the diagnostic yield of FB without fluoroscopic guidance was comparable with that reported earlier using fluoroscopy.

Effects of elastase inhibitor on the epithelial cell apoptosis in bleomycin-induced pulmonary fibrosis.

Alveolar epithelial cell injury and apoptosis is consistent findings in human idiopathic pulmonary fibrosis (IPF). Epithelial cell apoptosis is known to be induced by leukocyte elastase in vitro. The authors hypothesized that synthetic neutrophil elastase inhibitor, sivelestat (ONO-5046), can inhibit the bleomycin-induced pulmonary fibrosis in rats by blocking the apoptotic pathways in epithelial cells. Adult rats were injected with intratracheal bleomycin. Sivelestat was given for 13 days intraperitoneally after bleomycin treatments. Similar experiments were carried out in which A549 cells, a human alveolar type II epithelial cell line, were treated with bleomycin or neutrophil elastase. In rats, sivelestat decreased neutrophil counts and the cytokine-induced neutrophil chemoattractant (CINC)-1 in the bronchoalveolar lavage (BAL) fluid of bleomycin-treated rats. Sivelestat also decreased the bleomycin-induced lung inflammatory cell apoptosis by decreasing caspase-3 and -9 activities. In A549 cells, sivelestat decreased the elastase-induced epithelial cell apoptosis but not the bleomycin-induced epithelial cell apoptosis. Similarly, sivelestat inhibited the elastase-induced cell death but not the bleomycin-induced cell death in MTT assays. Sivelestat also inhibited the elastase-induced caspase-3 and -9 activities and cytochrome c release from the mitochondria but did not inhibit the bleomycin-induced caspase activities in A549 cells. In conclusion, bleomycin caused the lung inflammatory cell apoptosis through the caspase-9 and -3 pathways in rats. Sivelestat inhibited pulmonary fibrosis by blocking these mitochondria-mediated apoptotic pathways in bleomycin-treated rats and in elastase-treated A549 cells. These findings suggest that sivelestat can suppress the bleomycin-induced pulmonary fibrosis by blocking neutrophil chemotaxis and by inhibiting the neutrophil elastase-induced lung cell apoptosis in rats.