MicroRNA-574-5p Attenuates Acute Respiratory Distress Syndrome by Targeting HMGB1.

Acute respiratory distress syndrome (ARDS) is a critical condition with high mortality. HMGB1 (high-mobility group protein B1) is one of the key proinflammatory factors in the ARDS "inflammatory storm." According to previous studies, some microRNAs (miRNAs) play important roles in this process. We aimed to determine the contributing miRNAs targeting the expression and release of HMGB1. miRNA expression in the peripheral blood of patients with ARDS was measured by miRNA microarray. miRNAs targeting HMGB1 were screened and explored for further study. In LPS-induced cell and mouse ARDS models, we explored the effect of this miRNA on the expression and secretion of HMGB1 by Western blot, real-time qPCR, and ELISA. The effects of this miRNA on the NF-κB signaling pathway, proinflammatory cytokines, and NLRP3 (nod-like receptor protein 3) inflammasome were detected by Western blot and real-time qPCR. In ARDS models, microRNA-574-5p (miR-574-5p) expression could be induced by the TLR4/NF-κB pathway upon LPS stimulation. It could suppress the inflammatory response by targeting HMGB1. Enforcing the expression of miR-574-5p or HMGB1 siRNA silencing inhibits the activation of NF-κB signaling pathway and the NLRP3 inflammasome. Moreover, overexpression of HMGB1 reversed the antiinflammatory effect of miR-574-5p. In ARDS mice, overexpression of miR-574-5p suppresses alveolar leukocytes infiltration, interstitial edema, protein effusion, and inflammation. This study demonstrated that miR-574-5p provided negative feedback to LPS-induced inflammation and relieved ARDS. It may provide new therapeutic strategies for ARDS.

Clinical profile and surgical outcome for different types of chronic pulmonary aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) has been reclassified as several different subtypes, and the clinical features of the different types should be further investigated. Surgery is a remedial option for patients who experience pharmacological treatment failure, though more information about the effectiveness and prognosis of surgical treatment and perioperative medication for different types of CPA is needed. METHODS: This was a retrospective study of patients with proven CPA who underwent surgery between January 2001 and June 2018 at Nanjing Jinling Hospital. RESULTS: Sixty patients underwent surgery. The median age was 52.5 years (22-80), and chronic cavitary pulmonary aspergillosis (CCPA) accounted for the largest proportion of cases (46.7%). The most common presenting symptom was hemoptysis (70%). Many patients had underlying lung disease, including bronchiectasis (30%) and obsolete tuberculosis (TB) (21.7%). The surgical procedures included lobectomy (76.7%), wedge resection (16.7%), segmentectomy (5%) and pneumonectomy (1.7%). In total, 33 patients (62.3%) received perioperative antifungal treatment, all of whom improved or were cured. Conversely, 22 patients did not receive perioperative anti-Aspergillus treatment; among them, 3 patients with subacute invasive aspergillosis (SAIA) and 1 with CCPA experienced disease progression or died. CONCLUSIONS: Surgery is needed in some patients with refractory CPA. We consider that SAIA and CCPA patients may benefit from perioperative antifungal therapy. However, due to the limited number of patients in this study, more evidence is needed to draw a conclusion about this issue.

Role of the Aspergillus-Specific IgG and IgM Test in the Diagnosis and Follow-Up of Chronic Pulmonary Aspergillosis.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) has a high rate of misdiagnosis and has been reported to have an increasing rate of morbidity and mortality. In this article, we assessed the serum Aspergillus-specific IgG and IgM test in the diagnosis of patients with CPA. METHODS: A prospective study was conducted from January 2016 to July 2017 in Nanjing Jinling Hospital. Serum samples were collected from CPA patients (178 sera, 82 patients) and from non-aspergillosis patients (125 sera) with community-acquired pneumonia (CAP), active tuberculosis, bronchiectasis or lung tumors. Additionally, we included a control group of healthy patients(50 sera). Aspergillus-specific antibody detection was performed using a Dynamiker ELISA kit, and the results were compared with the value of galactomannan (GM) in bronchoalveolar lavage fluid (BALF). RESULTS: The sensitivity and specificity of the Aspergillus-specific IgG antibody in the diagnosis of CPA were 84.1 and 89.6%, respectively. These values were slightly higher compared to those obtained for the sensitivity and specificity using the BALF GM test (79.1 and 84.2%, respectively). However, the sensitivity and specificity of Aspergillus-specific IgM antibody were only 43.9 and 87.2%, respectively. Moreover, the positive rate of IgG in patients with subacute invasive aspergillosis (SAIA) was 87%, compared to the positive rates of IgG in CPA patients sick for 3-6 months (80.0%), 6-9 months (81.8%) and ≥9 months (80.0%). Meanwhile, the positive rate of IgM in SAIA patients was 63%, compared to the positive rate of IgM in CPA patients sick for 3-6 months (46.7%), 6-9 months (0%) and ≥9 months (0%), respectively. Furthermore, serum IgG levels decreased gradually in the majority of CPA patients who showed positive response to antifungal therapy, and IgG levels increased in two CPA patients when their disease worsened. CONCLUSION: A serum Aspergillus-specific IgG test is a valuable tool for the diagnosis of CPA and SAIA, while an Aspergillus-specific IgM test is only modestly specific for the diagnosis of SAIA. Overall, the variation trend of Aspergillus-specific IgG levels may reflect the therapeutic effectiveness in the long-term follow-up of CPA.

MMI-0100 ameliorates lung inflammation in a mouse model of acute respiratory distress syndrome by reducing endothelial expression of ICAM-1.

PURPOSE: ICAM-1 plays a critical role in the development of acute respiratory distress syndrome (ARDS). MK2 regulates the expression of ICAM-1 in human pulmonary microvascular endothelial cells. To explore whether the inhibition of MK2 activation has the same effect in experimental animals, MMI-0100, a peptide-mediated inhibitor of MK2, was used to verify whether MMI-0100 can ameliorate lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1. METHODS: In this study, C57BL/6 mice were randomly divided into three groups: a control group, an lipopolysaccharides (LPS) group, and an LPS plus MMI-0100 group. Mice were killed 24 hours after the administration of LPS and MMI-0100. The mouse lung tissue histopathology, wet/dry weight ratio (W/D), and the neutrophil count were used to measure the severity of lung inflammation in mice. The pulmonary microvascular endothelial cells (PMVECs) of the mice were isolated. The mRNA expression of ICAM-1 in mouse PMVECs was determined using RT-PCR, and the protein expression of MK2 and ICAM-1 in mouse PMVECs was analyzed using Western blotting and immunohistochemistry. RESULTS: We found that the level of phosphorylated MK2 in the LPS plus MMI-0100 group was reduced. Compared with the LPS group, the LPS plus MMI-0100 group of mice showed less severe inflammation, including a lower W/D and neutrophil count. The mRNA and protein expression of ICAM-1 in the LPS group was significantly higher than in the control group in mouse PMVECs, and the ICAM-1 level was reduced after the administration of MMI-0100. CONCLUSION: These data indicate that MMI-0100 ameliorates lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1.

Pentraxin 3 Gene Polymorphisms and Pulmonary Aspergillosis in Chronic Obstructive Pulmonary Disease Patients.

Background: Pentraxin 3 (PTX3) plays an important role in resistance to Aspergillus infections. Previous studies have suggested that PTX3 polymorphisms influence the risk of invasive aspergillosis among transplantation recipients. This study investigated the association between PTX3 gene polymorphisms and pulmonary aspergillosis in a chronic obstructive pulmonary disease (COPD) population. Methods: We included 173 consecutive inpatients with COPD. Thirty-six case patients were finally diagnosed with pulmonary aspergillosis. Among these, 25 case patients had invasive pulmonary aspergillosis (IPA), and 11 case patients had chronic pulmonary aspergillosis (CPA). Three single nucleotide polymorphisms (SNPs; rs2305619, rs3816527, and rs1840680) in the PTX3 gene were detected by polymerase chain reaction direct sequencing, and their associations with aspergillosis were evaluated. Plasma PTX3 levels were measured by enzyme-linked immunosorbent assay. Results: Three SNPs were consistent with Hardy-Weinberg equilibrium. The recessive model for SNP rs1840680 suggests that the AA homozygote is associated with a higher risk for pulmonary aspergillosis (both IPA and CPA) in COPD patients. However, for genotypic and allele frequencies of rs2305619 and rs3816527, no association was observed. The distribution of haplotypes (rs2305619 and rs3816527) also showed no significant differences. Plasma PTX3 levels significantly increased in IPA patients. In the IPA group, the rs1840680 AA genotype subjects showed lower plasma PTX3 levels than those harboring AG and GG genotypes. Conclusions: This study showed a significant association between PTX3 rs1840680 polymorphisms and the susceptibility of pulmonary aspergillosis in patients with COPD. Plasma PTX3 levels may be potentially used as indicators for the diagnosis of IPA in COPD patients.