Specialized Pro-resolution Mediators in Cystic Fibrosis Lung Disease

CF is caused by a mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) and results in airway surface liquid (ASL) dehydration, impaired muco-ciliary clearance, chronic pulmonary infection and inflammation leading to progressive lung destruction. Specialized Pro-Resolution Mediators (SPM’s) such as Lipoxins and Resolvins are SPM’s involved in the active resolution of inflammation. Previous work showed that Lipoxin A4 restores airway surface liquid height in CF bronchial epithelium. Our aim was to investigate the role of SPMs, including Lipoxin A4 and Resolvin D1 in CF airway disease. We studied the physiological effects of RvD1 in CF using primary CF alveolar macrophages and polarized, differentiated Primary CF and NuLi-1, and CuFi-1 cell lines as a bronchial epithelial model. We collected bronchoalveolar lavage (BAL) samples from young children with CF and controls at clinical baseline (SHIELD CF) and sputum from school aged children during CF Pulmonary Exacerbation (CFPE) (PRINCE Study). We report that Resolvin D1 restored ASL height in Primary CF bronchial epithelia and CuFi-1 cells. Resolvin D1 attenuated TNFα induced IL8 secretion in CuFi-1 cells. Furthermore Resolvin D1 improved phagocytic capacity and bacterial killing of Pseudomonas aeruginosa in primary CF alveolar macrophages. We demonstrate an imbalance in Lipoxin A4 (LXA4) versus Leukotriene B4 (LTB4) production in CF airways, despite the absence of infection, related to a deficiency of the LXA4 synthetic enzyme 15 Lipoxygenase-2 in CF macrophages. We have demonstrated that the levels of Resolvin D2 and 15-d-Prostaglandin J2 correlate strongly with the extent of recovery of premorbid FEV1 during CF pulmonary exacerbation. We have elucidated important beneficial physiological effects of SPMs in CF airway cells, shown defective class switching in children with CF compared to controls, and demonstrated a link between sputum SPM levels and lung function recovery during acute infection in CF. Our findings shed some light on the failure 23 to resolve inflammation in CF airways and suggest strong therapeutic potential for SPMs in CF

Physiological Impact of Abnormal Lipoxin A 4

Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation

Cognition in chronic kidney disease: a systematic review and meta-analysis

Background Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. Methods We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, in any research setting. We conducted a meta-analysis using random effects, expressed as standardised mean differences (SMD) with 95% confidence intervals (CI). Outcomes were performance in eight cognitive domains. Bias was assessed with the Newcastle-Ottawa Scale (NOS). Results We identified 44 studies reporting sufficient data for synthesis (51,575 participants). Mean NOS score for cohort studies was 5.8/9 and for cross-sectional 5.4/10. Studies were deficient in NOS outcome and selection due to poor methods reporting and in comparison group validity of demographics and chronic disease status. CKD patients (eGFR < 60 mL/min/1.73 m2) performed worse than control groups (eGFR ≥ 60 mL/min/1.73 m2) on Orientation & Attention (SMD –0.79, 95% CI, –1.44 to –0.13), Language (SMD –0.63, 95% CI, –0.85 to –0.41), Concept Formation & Reasoning (SMD –0.63, 95% CI, –1.07 to –0.18), Executive Function (SMD –0.53, 95% CI, –0.85 to –0.21), Memory (SMD –0.48, 95% CI, –0.79 to –0.18), and Global Cognition (SMD –0.48, 95% CI, –0.72 to –0.24). Construction & Motor Praxis and Perception were unaffected (SMD –0.29, 95% CI, –0.90 to 0.32; SMD –1.12, 95% CI, –4.35 to 2.12). Language scores dropped with eGFR (<45 mL/min/1.73 m2 SMD –0.86, 95% CI, –1.25 to –46; 30 mL/min/1.73 m2 SMD –1.56, 95% CI, –2.27 to –0.84). Differences in Orientation & Attention were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.62, 95% CI, –4.68 to –4.55). Concept Formation & Reasoning differences were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.27, 95% CI, –4.23 to –4.27). Differences in Executive Functions were greatest at eGFR < 30 mL/min/1.73 m2 (SMD –0.54, 95% CI, –1.00 to –0.08). Conclusions Cognitive changes occur early in CKD, and skills decline at different rates. Orientation & Attention and Language are particularly affected. The cognitive impact of CKD is likely to diminish patients’ capacity to engage with healthcare decisions. An individual’s cognitive trajectory may deviate from average

THE ROLE OF LIPOXIN A4 IN CYSTIC FIBROSIS LUNG DISEASE

International audienc

Physiological Impact of Abnormal Lipoxin A 4 Production on Cystic Fibrosis Airway Epithelium and Therapeutic Potential

International audienc

Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways

International audienc

Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways

International audienc