- 作者列表："Saferali A","Tang AC","Strug LJ","Quon BS","Zlosnik J","Sandford AJ","Turvey SE
BACKGROUND:Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity. METHODS:We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF. RESULTS:The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins. CONCLUSIONS:BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.
背景: 囊性纤维化 (CF) 以气道阻塞、感染和炎症导致的肺功能进行性下降为特征。CF患者特别容易受到各种病原体的呼吸道感染，并且CF中的炎症反应失调和延长。含有家族A、成员 1 (BPIFA1) 和BPIFB1 的BPI折叠是在上气道中表达的可能具有先天免疫活性的蛋白质。我们之前发现了与CF肺病严重程度相关的BPIFA1/BPIFB1 区域多态性。 方法: 我们评估了参与国际CF基因修饰者联盟 (n = 6,365) 的CF个体中是否复制了BPIFA1/BPIFB1 与肺部疾病严重程度的相关性。此外，我们研究了BPIFA1 和BPIFB1 蛋白可能改变CF中肺病的机制。 结果: 在一个独立的CF患者队列中，rs1078761 的G等位基因与肺功能降低的相关性得到了重复 (p = 0.001，n = 2,921)。并在全联盟的荟萃分析中 (p = 2。39x10-5，n = 6,365)。此外，我们发现与肺功能降低相关的rs1078761G也与CF患者唾液中BPIFA1 蛋白水平降低有关，但与BPIFB1 蛋白水平无关。功能测定表明，BPIFA1 和BPIFB1 不具有抗铜绿假单胞菌的抗菌作用，但可能在CF气道上皮细胞中具有免疫调节功能。使用RNAseq的基因表达谱鉴定了在CF气道上皮细胞中响应重组BPIFA1 和BPIFB1 蛋白治疗而改变的Rho gtp酶信号通路。 结论: BPIFA1 和BPIFB1 具有免疫调节活性，与低水平的这些蛋白相关的遗传变异可能增加CF肺病的严重程度。
METHODS::The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.
METHODS::Pneumonia is a common respiratory infectious disease that involves the inflammation of the pulmonary parenchyma. Periodontal disease is widespread and correlated with pneumonia. However, the relationship between periodontal treatment and clinical infectious outcomes in patients with pneumonia has remained undetermined. The aim of this study was to investigate the association between periodontal treatment and the risk of pneumonia events in the Taiwanese population. A nationwide population-based cohort study was conducted using data from the Taiwanese National Health Insurance Research Database (NHIRD). A total of 49,400 chronic periodontitis patients who received periodontal treatment from 2001 to 2012 were selected. In addition, 49,400 healthy individuals without periodontal diseases were picked randomly from the general population after propensity score matching according to age, gender, monthly income, urbanization, and comorbidities. The Cox proportional hazard regression analysis was adopted to assess the hazard ratio (HR) of pneumonia between the periodontal treatment cohort and the comparison cohort. The average ages of the periodontal treatment and comparison groups were 44.25 ± 14.82 years and 44.15 ± 14.5 years, respectively. The follow up durations were 7.66 and 7.41 years for the periodontal treatment and comparison groups, respectively. We found 2504 and 1922 patients with newly diagnosed pneumonia in the comparison cohort and the periodontal treatment cohort, respectively. The Kaplan-Meier plot revealed that the cumulative incidence of pneumonia was significantly lower over the 12 year follow-up period in the periodontal treatment group (using the log-rank test, p < 0.001). In conclusion, this nationwide population-based study indicated that the patients with periodontal treatment exhibited a significantly lower risk of pneumonia than the general population.
METHODS:OBJECTIVE:To describe the treatment of community-acquired pneumonia (CAP) in children under five years in Tanzania. METHODS:Between January and December 2017, children aged 2-59 months with chest radiography-confirmed CAP were enrolled. The parents were interviewed to collect information on the patients and home-based medication. Clinical information was derived from the patient files. Nasopharyngeal swab and blood samples were collected for isolation of the causative pathogens. Swab samples were analysed by quantitative PCR whereas blood samples were tested using BacT/Alert 3D. RESULTS:Overall, 109 children with CAP were included in this analysis. Provision of care to most children was delayed (median = 4.6 days). A quarter (26.6%) were given unprescribed/leftover antibiotics at home. Only one child had positive bacterial culture. Referrals were associated with nasopharyngeal carriage of Streptococcus pneumoniae (p = 0.003) and Haemophilus influenzae (p = 0.004). Of all admitted children, more than a quarter (n = 29) did not need to be hospitalised and inappropriately received injectable instead of oral antibiotics. CONCLUSION:We found high rates of home treatment, particularly with antibiotics. Appropriate health care was delayed for most children because of home treatment. Efforts are needed at the community level to improve awareness of antimicrobial resistance.