First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients.

BACKGROUND: Nivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or <1% in Part 1 of CheckMate 227. Here we report efficacy and safety results for the Asian subpopulation. METHODS: Patients with stage IV/recurrent NSCLC were randomized 1 : 1 : 1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy (PD-L1 ≥1%) or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Overall survival (OS), progression-free survival, objective response rate, duration of response, and safety were evaluated among patients in Japan, South Korea, and Taiwan. RESULTS: In the Asian subpopulation with PD-L1 ≥1%, 81 patients received nivolumab plus ipilimumab and 81 received chemotherapy. Median OS was not reached with nivolumab plus ipilimumab versus 24.8 months with chemotherapy; 3-year OS rate was 53% versus 37% [hazard ratio (HR), 0.72; 95% confidence interval (CI) 0.47-1.11]. The 3-year progression-free survival rate was 26% versus 7% (HR, 0.65; 95% CI 0.45-0.96), objective response rate was 56% versus 37%, and median duration of response was 29.0 months (95% CI 15.0 months-not reached) versus 6.9 months (95% CI 3.9-11.1 months). Similar results were observed regardless of tumor PD-L1 expression and in Japanese patients. Grade 3-4 treatment-related adverse events occurred in 40% of patients receiving nivolumab plus ipilimumab and 36% receiving chemotherapy, in the overall Asian subpopulation (tumor PD-L1 expression ≥1% and <1%); no new safety signals were identified. CONCLUSIONS: At 3-year follow-up, nivolumab plus ipilimumab provided durable long-term efficacy benefits versus chemotherapy regardless of tumor PD-L1 expression in the Asian subpopulation, including Japanese patients. Consistent with findings for all randomized patients, these data support the use of nivolumab plus ipilimumab as first-line treatment of Asian patients with advanced NSCLC.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

LINC00887 aggravates the malignant progression of glioma via upregulating CCND1.

OBJECTIVE: This study aims to explore the impact of LINC00887 on the malignant progression of glioma via upregulating CCND1. PATIENTS AND METHODS: LINC00887 and CCND1 levels in glioma patients in different tumor grades or metastasis statuses were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Kaplan-Meier curves were depicted for analyzing the prognostic potential of LINC00887 in glioma patients. Meanwhile, Pearson correlation test was conducted to assess the expression correlation between LINC00887 and CCND1 in glioma tissues. After knockdown of LINC00887 in LN229 and U251 cells, proliferative abilities were examined by cell counting kit-8 (CCK-8) and 5-Ethynyl-2'- deoxyuridine (EdU) assays. Subcellular distribution of LINC00887 was determined. Thereafter, RNA Binding Protein Immunoprecipitation (RIP) was performed to uncover the interaction between LINC00887 and CCND1. After α-amanitin induction in glioma cells overexpressing LINC00887, RNA degradation of CCND1 was examined at 0, 6, 12 and 24 h, respectively. Finally, the synergistic regulation of both LINC00887 and CCND1 on glioma proliferation was explored by CCK-8 assay. RESULTS: It was found that LINC00887 was upregulated in glioma tissues, especially in stage III+IV or metastatic glioma cases. Overall survival was remarkably worse in glioma patients expressing a high level of LINC00887 than those with a low level. CCND1 was upregulated in glioma tissues as well, showing a positive correlation to LINC00887. In addition, LINC00887 was mainly distributed in the cytoplasm and interacted with CCND1, and it shortened the half-life of CCND1. Moreover, the knockdown of LINC00887 inhibited glioma cell proliferation, and this inhibitory effect was abolished by overexpression of CCND1. CONCLUSIONS: LINC00887 is upregulated in glioma tissues, and it aggravates the malignant progression of glioma by upregulating CCND1.

The diagnosis of lung cancer in the era of interventional pulmonology.

Advances in bronchoscopic and other interventional pulmonology technologies have expanded the sampling procedures pulmonologist can use to diagnose lung cancer and accurately stage the mediastinum. Among the modalities available to the interventional pulmonologist are endobronchial ultrasound-guided transbronchial needles aspiration (EBUS-TBNA) and transoesophageal bronchoscopic ultrasound-guided fine-needle aspiration (EUS-B-FNA) for sampling peribronchial/perioesophageal central lesions and for mediastinal lymph node staging, as well as navigational bronchoscopy and radial probe endobronchial ultrasound (RP-EBUS) for the diagnosis of peripheral lung cancer. The role of the interventional pulmonologist in this setting is to apply these procedures based on the correct interpretation of clinical and radiological findings in order to maximise the chances of achieving the diagnosis and obtaining sufficient tissue for molecular biomarker testing to guide targeted therapies for advanced non-small cell lung cancer. The safest and the highest diagnosis-yielding modality should be chosen to avoid a repeat sampling procedure if the first one is non-diagnostic. The choice of site and biopsy modality are influenced by tumour location, patient comorbidities, availability of equipment and local expertise. This review provides a concise state-of-the art account of the interventional pulmonology procedures in the diagnosis and staging of lung cancer.

[Research progress in therapeutic action of mesenchymal stem cell in allergic rhinitis].

Allergic rhinitis (AR) is an allergic disease of nasal mucosa, currently the consensus has been reached that there is a Th1/Th2 imbalance in AR's pathogenesis, meanwhile there are defects in the number and/or function of Treg cells. Mesenchymal stem cells (MSCs) have characteristics of multiple differentiation potential, low immunogenicity and immunomodulation function, which can be migrated and implanted into the nasal inflammatory mucosal, recovering the Th1/Th2 immune balance and up-regulate the Treg cells by immunomodulatory function to improve AR. For the present, the treatment of AR by MSCs is basically at the animal experiment stage. This paper reviews the progress of MSCs in AR's treatment and provides a basis for the clinical treatment of MSCs.

[Clinical significance of continuous transfixion suture for nasal septum in septoplasty].

Objective:To systemically evaluate the clinical significance of continuous transfixion suture for nasal septum in septoplasty. Method:Forty patients with nasal septum deviation were randomly assigned to the suture group including 20 patients who underwent endoscopic septoplasty followed by continuous transfixion suture for nasal septum, or the nasal packing group including 20 patients who underwent endoscopic septoplasty followed by nasal packing. Two groups were compared for the visual analogue scale (VAS) scores for postoperative rhinalgia, headache, lacrimation, dysphagia and sleep disorder, changes in mucociliary transport time (MTT) before and after surgery, and postoperative capillary hemorrhage. Patients were followed up for 2 weeks to observe the short-term postoperative complications. Result:Mean VAS scores for rhinalgia, headache, lacrimation, dysphagia and sleep disorder were all higher in nasal packing group than those in suture group (P<0.05); compared to suture group, there was greater prolongation of MTT before and after surgery in packing group (P<0.05); there was significant difference between two groups in postoperative capillary hemorrhage volume (P<0.05); in the nasal packing group, nasal synechia, nasal dryness and hyposmia were observed in 1, 3 and 2 patients, respectively, within 2 weeks postoperatively, whereas no short-term complications were observed in the suture group. Conclusion:Use of continuous transfixion suture in place of nasal packing following septoplasty can significantly improve the postoperative symptoms, protect nasal mucociliary clearance, and reduce short-term postoperative complications.

[Value discussion of radical sinus surgery for difficult-to-treat rhinosinusitis].

Objective:To investigate the efficacy of radical sinus surgery (RSS) on difficult-to-treat rhinosinusitis(DTRS) with nasal polyps. Method: We retrospectively analyzed the clinical data of 26 patients with DTRS that treated with RSS and patients who were not treated with RSS in our hospital from August 2013 to June 2017.The effect of RSS were evaluated by comparing the CT Lund-Kennery score,endoscope Lund-Kennery score,global VAS score and dysosmia VAS score before operation and 6 months after operation. Result: RSS group had more severe Lund-Kennery score,global VAS score and dysosmia VAS score than non-RSS group,and also had more previous surgeries,higher ratio of olfactory region polyps,and higher ratio of co-existing asthma and allergic rhinitis. However RSS group had a lower ratio with pus anot than non-RSS group. The eosinophil count in periheral blood between two groups had no statistical significance. Six months after RSS,the score of endoscope Lund-Kennery,global VAS and dysosmia VAS dependence. 14 patients were successfully cured(53.8%), 12 patients showed improvement(46.2%), no invalid cases. Conclusion: The global symptoms and olfaction of DTRS patients can be improved by RSS combine individual perioperative drug therapy.

The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia.

Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia.

[RNA interference targeting DNA-PKcs inhibits glioma cells malignancies and enhances temozolomide sensitivity].

Objective: To investigate the effect of DNA dependent protein kinase catalytic subunit (DNA-PKcs) on glioma proliferation, invasion and temozolomide sensitivity, and also to explore the potential mechanisms. Methods: Human glioma cell lines H4 and U87 were chosen to carry out RNA interference transfection, and then divided into negative control group (blank group) and siRNA group (test group). The knockdown efficacy of DNA-PKcs siRNA was tested by quantitative PCR and Western blot. The MTS assay and Transwell assay were used to investigate the effect of DNA-PKcs knockdown on glioma cell growth and invasion, respectively. We also used MTS assay to investigate the IC(50) value of temozolomide in negative control group and siRNA groups. Result: Compared with blank group, DNA-PKcs specific siRNA significantly downregulated both mRNA and protein level of DNA-PKcs. MTS assay results demonstrated that 72-hours proliferation of test group were only 52.48%, 54.70% (H4) and 52.98%, 50.45% (U87) of the blank group's counterpart. Transwell assay results showed that the invasiveness abilities of blank and test groups were 1.00±0.03, 0.41±0.05, 0.39±0.04 (H4) and 1.00±0.02, 0.28±0.04, 0.27±0.04 (U87). Moreover, knockdown of DNA-PKcs significantly decreased the temozolomide IC(50) value (H4: 249±27, 97±39, 88±35; U87: 485±41, 86±49, 73±38). Further we applied the Western blot to reveal the mechanism of inhibitory effect of DNA-PKcs knockdown on glioma malignancies and temozolomide sensitivity. We found that downregulation of DNA-PKcs reduced the activity of AKT signal and the expression of its downstream effectors, such as c-Myc, MMP9, and Survivin. Conclusion: RNA interference targeting DNA-PKcs could inhibit glioma malignancies and enhance temozolomide sensitivity. The inhibitory effect of DNA-PKcs knockdown on those biological activities were mainly through inhibition of AKT signal and its downstream effectors.

[Comparison of the anterior corneal asphericity after small incision lenticule extraction and femtosecond laser in situ keratomileusis].

OBJECTIVE: To evaluate and compare the anterior corneal asphericity after small incision lenticule extraction(SMILE)and femtosecond laser in situ keratomileusis(FS-LASIK). METHODS: In this case-control study, 45 subjects who underwent SMILE operation comprised the study group, and 33 subjects with FS-LASIK operation comprised the control group. The asphericity coefficient Q-value of the right eyes in both groups was measured at diameters of 6, 7, 8 and 9 mm, respectively, before surgery and at 1 day, 1 week, 1 month and 6 months following surgery. The correlation between the variation of Q-value and the central cutting depth was analyzed. RESULTS: The Q-value of anterior corneal surface was 0.85 ± 0.31, 0.80±0.28, 0.69±0.25 and 0.51±0.23 after SMILE, and 1.13±0.56, 1.01±0.47, 0.80±0.39 and 0.51±0.31 after FS-LASIK at 1 week. In both groups, the Q-value was significantly different before and after surgery(P< 0.05); there were interaction effects between the operation method and time; the difference between the two groups at 6-mm and 7-mm diameters was statistically significant(P<0.05). The variation of the Q-value before and after operation(ΔQ)showed significant difference(P6mm=0.004, P7mm=0.014)between the two groups at 6-mm and 7-mm diameters. The cap diameter of the SMILE group was smaller than that of the FS-LASIK group, but the cutting depth was larger. There was no correlation between ΔQ and the cap/disc diameter. It showed a linear relationship(P<0.05)between ΔQ and the central cutting depth at all examined diameters in the two groups, and the relation degree in the FS-LASIK group was superior to the SMILE group. CONCLUSIONS: Both SMILE and FS-LASIK operations can change the negative Q-value of the anterior corneal surface to the positive. The impact of SMILE on the asphericity is smaller than that of FS-LASIK. (Chin J Ophthalmol, 2016, 52: 681-685).

[An analysis of changes in posterior corneal elevation and relevant factors after small incision lenticule extraction].

OBJECTIVE: To investigate changes in posterior corneal elevation after small incision lenticule extraction (SMILE) and related factors. METHODS: Retrospective case series study. Eighty-three eyes of 44 myopic patients undergoing SMILE were examined with the Pentacam preoperatively, and at 1 day, 1 month, 3 months, and 6 months postoperatively. Posterior corneal elevation at the corneal apex and 0°, 45°, 90°, 135°, 180°, 225°, 270° and 325° points of the 2 mm and 6 mm diameter (total, 17 points) was analyzed. RESULTS: The changes in posterior corneal elevation at 1 day, 1 month, 3 months, and 6 months were(-1.72±2.59), (-0.98±2.37), (-0.45±1.81) and (-0.25±2.20) µm, respectively, at the corneal apex. The results were statistically significant (t=6.07, 3.75, 6.07; P<0.05), except 6 months. The changes in posterior corneal elevation were (-1.42±2.06),(-0.69±1.86), (-0.30±1.50) and(-0.22±1.58) µm, respectively, in the 2 mm circle. The results of 1 day and 1 month were statistically significant (t=6.28, 6.28, P<0.05). The changes in posterior corneal elevation were (1.48±1.47),(0.98±1.32),(0.90±1.31) and (0.90±1.16) µm, respectively, in the 6 mm circle .The results were totally statistically significant (t=6.28, 6.28, P<0.05). There were statistically significant differences between 1 month and 1 day postoperatively in the corneal apex, 2 mm and 6 mm circles. The changes were (0.75±2.55),(0.73±1.97) and(-0.50±1.60) µm. There were statistically significant differences between 3 months and 1 month postoperatively in the corneal apex and 2 mm circle. The changes were (0.53±2.22) and (0.39±1.80) µm. No significant change was found in the 6 mm circle. Between postoperative 6 months and 3 months, there were no statistically significant differences. The spherical equivalent, intraocular pressure, ablation depth, residual bed thickness, corneal hysteresis, and corneal resistance factor had no obvious correlation with the changes in posterior corneal elevation. CONCLUSIONS: After SMILE, the surrounding cornea was slightly forward, while the central posterior cornea was slightly backwards, and returned gradually. The spherical equivalent, intraocular pressure, ablation depth, residual bed thickness, corneal hysteresis, and corneal resistance factor had no obvious correlation with the changes in posterior corneal elevation. (Chin J Ophthalmol, 2016, 52: 494-498).

[Strategy of the diagnosis and treatment for hydrocephalus associated with acoustic neuroma].

OBJECTIVE: To describe and analyze the strategy of the diagnosis and treatment for acoustic neuroma associated with hydrocephalus. METHODS: A retrospective review was performed in 29 patients with hydrocephalus associated with acoustic neuroma form Apr. 2004 to Apr. 2015. The patients' clinical information, the types of the hydrocephalus, the treatment and the prognosis of the hydrocephalus were recorded. RESULTS: There were 20 patients with obstructive hydrocephalus and 9 patients with communicating hydrocephalus preoperatively. Among the 29 cases, 3 patients had ventriculoperitoneal shunts, 5 patients had external ventricular drains, the remaining 21 patients had no further managements for hydrocephalus; after removing the acoustic neuroma, the hydrocephalus improved in 10 cases, the ventricle unchanged in 10 cases among the obstructive hydrocephalus group, the ventricle unchanged in all 9 cases among the communicating hydrocephalus group. Nineteen cases were diagnosed with communicating hydrocephalus and 10 cases with obstructive hydrocephalus postoperatively. CONCLUSIONS: Among the patients of acoustic neuroma associated with hydrocephalus, communicating hydrocephalus is more common than obstructive hydrocephalus. The optimal management of acoustic neuroma associated with hydrocephalus is complete removal of the tumor, with treatment only for patients with persistent hydrocephalus.

Treatment outcome of patients with isoniazid mono-resistant tuberculosis.

Isoniazid mono-resistance is the most common first-line drug resistance in tuberculosis (TB), but its treatment outcome remains unclear. From January 2004 to October 2011, 425 (5.1%) of 8414 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan were identified as having isoniazid mono-resistant TB. Among them, 395 (92.9%) were included and followed up for 2 years after complete treatment. Although 328 (83.0%) patients were successfully treated, 67 (17.0%) had unfavourable outcomes, including death in 56 (14.2%) and treatment failure in 11 (2.8%). The treatment success rate was similar in patients with high-level and low-level isoniazid-resistant TB (82.2% versus 83.4%, p 0.785) and among those taking anti-TB treatment with and without isoniazid (83.1% versus 83.0%, p 1.000). Patients without rifampicin interruption had lower risk of unfavourable outcome (14.3% versus 37.0%, p <0.001), especially those with low-level isoniazid resistance (11.5% versus 56.5%, p <0.001). Supplementation with a new-generation fluoroquinolone improved treatment success (60.0% versus 12.5%, p 0.003). The presence of cavitary lesions was significantly associated with a higher relapse rate (4.1% versus 0.0%, p 0.006) and extended treatment of 7-9, 10-12 and >12 months had less relapse than 6-month treatment (3.2%, 0%, 3.7% and 25.0%, respectively, p 0.037). Multivariate Cox proportional hazards analysis revealed that co-morbidity with cancer (hazard ratio, 2.43) and rifampicin interruption (hazard ratio 1.91) were independent factors associated with unfavourable outcomes. Treatment throughout with rifampicin and extended treatment for cavitary disease are crucial for improving outcomes in patients with isoniazid mono-resistant TB.

Factors associated with subsequent nontuberculous mycobacterial lung disease in patients with a single sputum isolate on initial examination.

Very few studies have focused on the outcome and management of patients with a single sputum isolate of nontuberculous mycobacterium (NTM) on initial examination. Patients with a single isolate of Mycobacterium avium complex (MAC), M. chelonae-abscessus, M. kansasii, or M. fortuitum from at least three sputum samples collected within 1 month were retrospectively identified. Those with follow-up sputum samples within 1 year were included in the analysis. Among the 202 patients included, M. fortuitum (n = 71, 35.1%) and MAC (n = 70, 34.7%) were the most common NTM species isolated, followed by M. chelonae-abscessus (n = 40, 19.8%) and M. kansasii (n = 21, 10.4%). The mean clinical follow-up period was 26.2 months. Forty-four patients (21.8%) had subsequent positive cultures of the same NTM species, while eight (4.0%) had bronchiectasis and developed NTM lung disease (NTM-LD). Neither patients without bronchiectasis nor those with M. fortuitum subsequently developed NTM lung disease. Among bronchiectatic patients with NTM other than M. fortuitum, age ≤65 years (p 0.006, OR 32.13), malignancy (p 0.048, OR 14.35), and initial radiographic score >2 (p 0.027, OR 20.06) were associated with subsequent NTM-LD. In all of the NTM patients, bronchiectasis (p <0.001, OR 5.46) and age ≤65 years (p 0.002, OR 3.29) were significantly associated with subsequent positive NTM culture. In patients with a single isolation of NTM from respiratory specimens, the presence of bronchiectasis and younger age indicates higher risk of subsequent culture-positivity and NTM-LD. Single isolation of M. fortuitum is of little clinical significance. Other patients with NTM, younger age, and more severe radiographic pulmonary lesion also warrant further attention.

Isolated familial pneumothorax in a Taiwanese family with Birt-Hogg-Dubé syndrome.

Primary spontaneous pneumothorax usually occurs as a sporadic event, but may be clustered in certain families with an underlying inherited disorder. Birt-Hogg-Dubι (BHD) syndrome is a rare autosomal dominant disease accounting for familial pneumothorax. BHD syndrome, caused by mutation of the folliculin gene, is characterized by skin fibrofolliculoma, pulmonary cysts, pneumothorax, and renal cancer. We describe a BHD-affected Taiwanese family with clinical and genetic study. A rare mutation of the folliculin gene was detected in the patient and members with pulmonary cysts or pneumothorax, but no skin or renal lesions were found. This mutation was reported in a Taiwanese family and might indicate a pneumothorax-predominant phenotype. Isolated pneumothorax is an uncommon initial presentation of BHD syndrome. Family history should be carefully reviewed when managing a patient with pneumothorax.

Elastase induced lung epithelial cell apoptosis and emphysema through placenta growth factor.

Chronic pulmonary obstructive disease (COPD) is the fourth leading cause of death worldwide, however, the pathogenic factors and mechanisms are not fully understood. Pulmonary emphysema is one of the major components of COPD and is thought to result from oxidative stress, chronic inflammation, protease-antiprotease imbalance and lung epithelial (LE) cell apoptosis. In our previous studies, COPD patients were noted to have higher levels of placenta growth factor (PlGF) in serum and bronchoalveolar lavage fluid than controls. In addition, transgenic mice overexpressing PlGF developed pulmonary emphysema and exposure to PlGF in LE cells induced apoptosis. Furthermore, intratracheal instillation of porcine pancreatic elastase (PPE) on to PlGF wild type mice induced emphysema, but not in PlGF knockout mice. Therefore, we hypothesized that PPE generates pulmonary emphysema through the upregulation of PlGF expression in LE cells. The elevation of PlGF then leads to LE cell apoptosis. In the present study, we investigated whether PPE induces PlGF expression, whether PlGF induces apoptosis and whether the downstream mechanisms of PlGF are related to LE cell apoptosis. We found that PPE increased PlGF secretion and expression both in vivo and in vitro. Moreover, PlGF-induced LE cell apoptosis and PPE-induced emphysema in the mice were mediated by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways. Given these findings, we suggest that the increase in PlGF and PlGF-induced JNK and p38 MAPK pathways contribute to PPE-induced LE cell apoptosis and emphysema. Regulatory control of PlGF and agents against its downstream signals may be potential therapeutic targets for COPD.