Angiotensin-converting enzyme (ACE) enhances the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which contribute to the pathogenesis of hypoxic pulmonary hypertension (HPH). Previous reports have demonstrated that hypoxia upregulates ACE expression, but the underlying mechanism is unknown. Here, we found that ACE is persistently upregulated in PASMCs on the transcriptional level during hypoxia. Hypoxia-inducible factor 1alpha (HIF-1alpha), a key transcription factor activated during hypoxia, was able to upregulate ACE protein expression under normoxia, whereas knockdown of HIF-1alpha expression in PASMCs inhibited hypoxia-induced ACE upregulation. Furthermore, HIF-1alpha can bind and transactivate the ACE promoter directly. Therefore, we report that ACE is a novel target of HIF-1alpha. Recently, a homolog of ACE, ACE2, was reported to counterbalance the function of ACE. In contrast to ACE, we found that ACE2 mRNA and protein levels increased during the early stages of hypoxia and decreased to near-baseline levels at the later stages after HIF-1alpha accumulation. Thus HIF-1alpha inhibited ACE2 expression, and the accumulated ANG II catalyzed by ACE is a key mediator in the downregulation of ACE2 by HIF-1alpha. Moreover, a reduction of ACE2 expression in PASMCs by RNA interference was accompanied by significantly enhanced proliferation and migration during hypoxia. We conclude that ACE is directly regulated by HIF-1alpha, whereas ACE2 is regulated in a bidirectional way during hypoxia and may play a protective role during the development of HPH. In sum, these findings contribute to the understanding of the pathogenesis of HPH.

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Our CARE study highlights that asthma epidemic in mainland China should be paid more attention.

Interleukin-17 (IL-17) is involved in protection against extracellular bacteria. However, IL-17 is likely to be deleterious to a host with chronic pulmonary Pseudomonas aeruginosa infection. The role of IL-17 during acute pulmonary P. aeruginosa infection remains unknown. Here, we evaluated the role that IL-17 plays in acute pulmonary P. aeruginosa infection and the source of the interleukin. The production of IL-17 increased rapidly after acute pulmonary P. aeruginosa infection in mice. We subsequently examined the role of IL-17 in acute infection and found 100 times more bacteria in the bronchoalveolar lavage fluid of mice treated with an IL-17-neutralizing antibody compared with the IgG(2a) -treated mice after 16 h of infection. The main infiltrating cells in the anti-IL-17-treated mice were lymphocytes rather than neutrophils. Consistently, more tissue damage and pathological changes in the lung were observed in the anti-IL-17-treated mice. We also found that Th17 cells are one of the sources of IL-17. We conclude that the early production of IL-17 plays a protective role during acute pulmonary P. aeruginosa infection in mice and that Th17 cells are one of the sources of IL-17 during acute pulmonary P. aeruginosa infection. Altogether, IL-17 and Th17 cells contribute to the pathogenesis of acute pulmonary P. aeruginosa infection in vivo.

Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS). ACE2 plays a critical counterbalancing role by degrading angiotensin II (Ang II) to Ang 1-7. Recent studies suggest that RAS influences tumor growth and development by its paracrine effects on the tumor microenvironment. Epithelial‑mesenchymal transition (EMT) is now thought to be a process that plays a fundamental role in tumor progression and metastasis. In the present study, we investigated the role of ACE2 in lung cancer metastasis and the mechanism of EMT. This is the first study to elucidate the mechanism through which the overexpression of ACE2 in the A549 lung cancer cell line decreases metastasis formation in vivo and upregulates the expression of E-cadherin both in vitro and in vivo. We also observed the downregulation of vimentin, which supports a role of ACE2 in influencing EMT in lung cancer. Further analysis indicated that ACE2 abrogated the upregulation of TGF-β1-induced EMT markers, such as vimentin and α-smooth muscle actin (αSMA) in vitro in A549 cells. Finally, exposing A549 cells stably expressing ACE2 to DX600, an inhibitor of ACE2, recovered the sensitivity of lung cancer cells to TGF-β1-mediated induction of EMT. Our study demonstrated that ACE2 attenuated the metastasis of lung cancer and may serve as a target for new strategies to inhibit EMT in cancer cells.

ObjectiveThis meta-analysis aimed to comprehensively examine the relationship between the clinicopathological and demographical characteristics and ALK rearrangements in patients with non-small cell lung cancer (NSCLC).Methods and Main FindingsIn total, 62 qualified articles including 1178 ALK rearranged cases from 20541 NSCLC patients were analyzed, and the data were extracted independently by two investigators. NSCLC patients with ALK rearrangements tended to be younger than those without (mean difference: −7.16 years; 95% confidence interval (95% CI): −9.35 to −4.96; P<0.00001), even across subgroups by race. Compared with female NSCLC patients, the odds ratio (OR) of carrying ALK rearrangements was reduced by 28% (95% CI: 0.58–0.90; P = 0.004) in males, and this reduction was potentiated in Asians, yet in opposite direction in Caucasians. Likewise, smokers were less likely to have ALK rearrangements than never-smokers (OR = 0.33; 95% CI: 0.25–0.44; P<0.00001), even in race-stratified subgroups. Moreover, compared with NSCLC patients with tumor stage IV, ALK rearrangements were underrepresented in those with tumor stage I–III (OR = 0.58; 95% CI: 0.44–0.78; P = 0.0002). Patients with lung adenocarcinomas had a significantly higher rate of ALK rearrangements (7.2%) than patients with non-adenocarcinoma (2.0%) (OR = 2.25; 95% CI: 1.54–3.27; P<0.0001).ConclusionOur findings demonstrate that ALK rearrangements tended to be present in NSCLC patients with no smoking habit, younger age and tumor stage IV. Moreover, race, age, gender, smoking status, tumor stage and histology might be potential sources of heterogeneity.

The screening of a person at risk for chronic obstructive pulmonary disease (COPD) and timely treatment may provide opportunities to delay the progressive destruction of lung function. Therefore, a model to predict the disease is required. We hypothesized that demographic and clinical information in combination with genetic markers would aid in the prediction of COPD development, prior to its onset. The aim of the present study was to create a predictive model for COPD development. Demographic, clinical presentation and genetic polymorphisms were recorded in COPD patients and control subjects. Nighty-six single-nucleotide polymorphisms of 46 genes were selected for genotyping in the case-control study. A predictive model was produced using logistic regression with a stepwise model-building approach and was validated. A total of 331 patients and 351 control subjects were included. The logistic regression identified the following predictors: Gender, respiratory infection in early life, low birth weight, smoking history and genotype polymorphisms (rs2070600, rs10947233, rs1800629, rs2241712 and rs1205). The model was established using the following formula: COPD = 1/[1 + exp (-2.4933-1.2197 gender + 1.1842 respiratory infection in early life + 2.4350 low birth weight + 1.8524 smoking - 1.1978 rs2070600 + 2.0270 rs10947233 + 1.1913 rs10947233 + 0.6468 rs1800629 + 0.5272 rs2241712 + 0.4024 rs1205)] (when the value is >0.5). The Hosmer-Lemeshow test showed no significant deviations between the observed and predicted events. Validation of the model in 50 patients showed a modest sensitivity and specificity. Therefore, a predictive model based on demographic, clinical and genetic information may identify COPD prior to its onset.

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