Crosstalk between the Akt/mTORC1 and NF-κB signaling pathways promotes hypoxia-induced pulmonary hypertension by increasing DPP4 expression in PASMCs.

Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5-20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKß separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/ß, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10-500 µM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1-5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats.

Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening (VS) of potential IP-PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.

Incidence and risk factors of chronic thromboembolic pulmonary hypertension in patients with diagnosis of pulmonary embolism for the first time in real world.

BACKGROUND: The incidence and risk factors of chronic thromboembolic pulmonary hypertension (CTEPH) in patients with acute pulmonary embolism (PE) have been well reported. However, in real world, patients diagnosed with PE for the first time were usually composed of acute PE, sub-acute PE, and chronic PE, and the cumulative incidence and risk factors of CTEPH in this cohort were still unknown. METHODS: A prospective, long-term, follow-up study was conducted to assess the incidence of symptomatic CTEPH in consecutive patients with PE diagnosed for the first time. Patients with unexplained persistent dyspnea during follow-up underwent transthoracic echocardiography and, if the findings indicated pulmonary hypertension, ventilation-perfusion lung scanning and right heart catheterization. CTEPH was confirmed if perfusion defects were present, mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary artery wedge pressure (PAWP) ≤15 mmHg. RESULTS: The cumulative incidence of CTEPH in patients with PE diagnosed for the first time was 11.2% at 3 months, 12.7% at 1 year, 13.4% at 2 years, and 14.5% at 3 years. The following factors increased the risk of CTEPH: time from symptoms to treatment of PE ≥1 month (odds ratio (OR), 14.77), intermediate (OR, 37.63) to high risk PE (OR, 39.81), segmental and sub-segmental branch location of embolism (OR, 8.30) and PE-related primary risk factors (OR, 5.01). 9.4% of CTEPH patients developed from acute PE, and 90.6% from sub-acute and chronic PE. CONCLUSIONS: In real world, CTEPH is a relatively common and serious complication in PE patients diagnosed for the first time. Early diagnosis and treatment of PE will decrease the incidence of CTEPH in these unspecified patients.

Interventional therapy in sarcoidosis-associated pulmonary arterial stenosis and pulmonary hypertension.

BACKGROUNDS: Pulmonary sarcoidosis is often complicated by pulmonary hypertension, a complication that is associated with increased disability and mortality. To this point, however, little progress has been made in the treatment of sarcoidosis associated with pulmonary hypertension (SAPH). METHODS: A prospective study was performed on 72 consecutive Chinese sarcoidosis patients followed at an outpatient clinic. The patients were evaluated by Doppler echocardiography and computed tomography pulmonary angiography. SAPH was confirmed by right heart catheterisation. The clinical parameters were compared before and 2 months after treatment with oral glucocorticoids. Eight stage III and IV patients with moderate to severe proximal pulmonary arterial stenosis (PAS) and SAPH underwent interventional therapy (IT) after prednisone treatment and were followed up at 3-month intervals. RESULTS: After 2 months of prednisone treatment, 32 stage III and IV patients continued to display varying degrees of PAS and SAPH. Eight patients underwent IT without severe complications and made improvements in pulmonary arterial pressure, pulmonary vascular resistance, arterial oxygen saturation and WHO functional classification, with the improvements lasting more than 3 months. CONCLUSIONS: PAS caused by external compression in sarcoidosis is a significant reason for SAPH. IT is effective and safe in the treatment of PAS and SAPH.

Resistance to epithelial growth factor receptor tyrosine kinase inhibitors in a patient with transformation from lung adenocarcinoma to small cell lung cancer: A case report.

First-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the treatment of non-small cell lung cancer (non-SCLC) with EGFR-sensitive mutations. However, acquired resistance to these drugs was inevitable. The transformation of lung adenocarcinoma to SCLC following treatment with EGFR-TKIs is a rare phenomenon that contributes to resistance to EGFR-TKIs. The present case concerns a 74-year-old man previously diagnosed with and treated for pneumonia; however, this was later pathologically confirmed as lung adenocarcinoma by transbronchial lung biopsy. Deletion of exon 19 of EGFR was identified by next-generation sequencing technology. The patient improved markedly when treated with gefitinib, but relapsed after 1 year, with markedly increased serum levels of neuron-specific enolase (NSE). Transformation to SCLC was detected by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) re-biopsy, which was negative for the deletion of exon 19 of EGFR. The patient was positive for vimentin expression and refractory to etoposide and cisplatin chemotherapy, and succumbed to the disease 18 months after diagnosis. Transformation of the disease from adenocarcinoma to SCLC may have been due to cancer heterogeneity. Re-biopsy is therefore important in EGFR-TKI-resistant patients for genetic and histological re-evaluation. NSE serum levels may also be useful for detecting early SCLC transformation.

Treatment of Pulmonary Arterial Hypertension Using Initial Combination Therapy of Bosentan and Iloprost.

BACKGROUND: Monotherapy and sequential combination therapy have been widely used in the treatment of pulmonary arterial hypertension (PAH). There is limited evidence for initial combination therapy in patients with PAH, particularly those with World Health Organization (WHO) functional class III or IV. METHODS: Twenty-seven consecutive treatment-naive PAH subjects with WHO functional class III or IV PAH were randomized into 3 groups with a 1:1:1 ratio: a combination therapy group with 125 mg of bosentan twice daily plus 10 µg of iloprost 4-6 times/d; a bosentan monotherapy group with 125 mg of bosentan twice daily; and a iloprost monotherapy group with 10 µg of iloprost 4-6 times/d. Clinical and hemodynamic data were collected at baseline, 6 weeks, and 3 months. The primary end point was the change in the 6-min walk distance (6MWD) from baseline values. RESULTS: At baseline, there were no differences in demographics, WHO classification, hemodynamics, classification of PAH, or 6MWD among the 3 groups. The 6MWD significantly improved in the combination therapy group compared with the bosentan monotherapy and iloprost monotherapy groups at week 6 (P = .001) and after 3 months (P < .001), respectively. Secondary end points significantly improved in the combination therapy group for mean pulmonary artery pressure, cardiac index, and WHO functional classification after 3 months of treatment and for N-terminal pro-brain natriuretic peptide, Minnesota Living with Heart Failure questionnaire scores, and PaO2 after 6 weeks and 3 months of treatment, compared with the monotherapy groups. CONCLUSIONS: Initial combination therapy in treatment-naive PAH subjects with WHO functional class III or IV can significantly improve 6MWD, hemodynamics, and quality of life compared with monotherapy. Further studies with large samples and placebo controls are required to assess the tolerability and efficacy of initial combination therapy in patients with PAH. (ClinicalTrials.gov registration NCT01712997).

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI-resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers.