Modified and simplified clinically important deterioration: multidimensional indices of short-term disease trajectory to predict future exacerbations in patients with chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Various prediction indices based on the single time point observation have been proposed in chronic obstructive pulmonary disease (COPD), but little was known about disease trajectory as a predictor of future exacerbations. Our study explored the association between disease trajectory and future exacerbations, and validated the predictive value of the modified and simplified short-term clinically important deterioration (CID). METHODS: This study was a multicenter, prospective observational study. Patients with COPD were recruited into our study and followed up for 18 months. The modified CID (CID-C) was defined as a decrease of 100 mL in forced expiratory volume in 1 second (FEV1), or suffering exacerbations, or increase of 2 units in COPD Assessment Test (CAT) during the first 6 months follow-up. Simplified CID was defined when excluding CAT from the CID-C model. RESULTS: A total of 127 patients were enrolled in our final analysis. Compared with patients without exacerbations during the period of the 6th to the 18th month, patients with exacerbations were more likely to have frequent short-term exacerbations in the first 6 months (2.14 versus 0.21, p < 0.001). The short-term exacerbations were the best predictor for future exacerbations [odds ratio (OR): 13.25; 95% confidence interval: 5.62-34.67; p < 0.001], followed by the history of exacerbation before study entry, short-term changes in FEV1 and CAT. CID-C and Simplified CID were both significantly associated with exacerbations (OR: 7.14 and 9.74, both p < 0.001). The receiver operating characteristic curves showed that the Simplified CID had slightly better predictive capacity for future exacerbation than CID-C (0.754 versus 0.695, p = 0.02). CONCLUSION: Disease trajectory, including both the CID-C and the Simplified CID had significant predictive value for future exacerbations.The reviews of this paper are available via the supplemental material section.

Microarray Analysis of Long Non-Coding RNAs in Lung Tissues of Patients with COPD and HOXA-AS2 Promotes HPMECs Proliferation via Notch1.

Background and Objectives: Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of many diseases, including cancer, pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). In this study, we intended to identify the differentially expressed lncRNAs and the role of HOXA cluster antisense RNA 2 (HOXA-AS2) in patients with COPD. Methods: We analyzed lncRNA profiles of three non-COPD and seven COPD patients' lungs via microarray and then validated the expression of the top differentially expressed lncRNAs by using real-time polymerase chain reaction (PCR). To identify the mechanism of HOXA-AS2 during COPD pathogenesis and endothelial cell proliferation, we knocked down and overexpressed HOXA-AS2 with siRNA and lentivirus transfection approach in human pulmonary microvascular endothelial cells (HPMECs). Results: Among 29,150 distinct lncRNA transcripts, 353 lncRNAs were significantly (≥2-fold change and P<0.05) upregulated and 552 were downregulated in COPD patients. The fold change of HOXA-AS2 is 9.32; real-time PCR confirmed that HOXA-AS2 was downregulated in COPD patients. In in vitro experiments, cigarette smoke extract (CSE) treatment reduced the expression of HOXA-AS2 and cell proliferation of HPMECs. Knocking down HOXA-AS2 inhibited HPMECs proliferation and the expression of Notch1 in HPMECs. Overexpressing Notch1 could partly rescue the inhibition of cell viability induced by the silence of HOXA-AS2. Conclusion: Our results demonstrated that differentially expressed lncRNAs may act as potential molecular biomarkers for the diagnosis of COPD, and HOXA-AS2 was involved in the pathogenesis of COPD by regulating HPMECs proliferation via Notch1, which may provide a new approach for COPD treatment.

Calcitonin gene-related peptide exerts anti-inflammatory property through regulating murine macrophages polarization in vitro.

Acute lung injury (ALI) is a condition resulting from direct or indirect lung injury associated with high mortality and morbidity. The phenotype of macrophages in lung contributes to the pathological progress of ALI. Calcitonin gene-related peptide (CGRP) is one of the most abundant neuropeptides in lung, and attenuates lipopolysaccharide (LPS)-induced ALI in rats. However, the exact effect of CGRP on the activation of macrophages remains unknown. Here we investigate the effect of CGRP on the macrophages activation and inflammation in murine macrophages in vitro. We found that LPS increased the expression of CGRP in a LPS-induced ALI murine model and LPS-stimulated murine macrophages. Although CGRP didn't alter the expression of tumor necrosis factor-α (a marker of pro-inflammatory phenotype of macrophages, M1 macrophages) or Arginase 1 (Arg1, a marker of M2 macrophages) in non-differentiated macrophages, CGRP significantly reduced the NLRP3 and pro-IL-1ß mRNA expression induced by LPS, as well as NLRP3 protein and IL-1ß secretion induced by LPS+ATP in macrophages in vitro. On the other hand, CGRP dramatically enhanced the Arg1 expression and activity induced by IL-4 in the time- and dose-dependent manners. CGRP also promoted the expression of markers of M2 macrophages (IL-10, Fizz1 and Mrc1) induced by IL-4 in murine macrophages. These effects of CGRP were also observed in primary murine peritoneal macrophages. In addition, we found that CGRP regulated macrophages polarization partially through calmodulin, PKC and PKA pathways. Specifically, CGRP could inhibit the degradation of I-κB induced by LPS, and enhance the phosphorylation of STAT6 induced by IL-4 in macrophages. In conclusion, our results indicate that CGRP regulates macrophage polarization and inhibits inflammation in murine macrophages.