Nuclear factor-kappaB (NF-B) plays a central role in regulating key proinflammatory mediators. The activation of NF-B is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-B activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-␣) and incubated with AZM. The nuclear NF-B-DNA binding activity, the levels of inhibitory kappaB-alpha (IB-␣) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-␣ increased the activation of NF-B, which was suppressed by the addition of AZM. Increased activation of NF-B was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-␣ stimulation also increased the degradation of IB-␣, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants. (Pediatr Res 62: [483][484][485][486][487][488] 2007)
Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti‐TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.
Objectives: To study the association between angiopoietin 2 (Ang2) concentrations in tracheal aspirates (TAs) and adverse outcome (bronchopulmonary dysplasia (BPD)/death) in ventilated premature infants (VPIs) and modulation of Ang2 concentrations with dexamethasone (Dex) use.Study Design: Serial TA samples were collected on days 1, 3, 5 and 7, and Ang2 concentrations were measured. Ang2 TA concentrations were compared prior to and after 48 to 72 h of using Dex.Result: A total of 151 TA samples were collected from 60 VPIs. BPD was defined as the oxygen requirement at 36 weeks postmenstrual age (PMA). Twelve infants (mean ± s.d.) (gestational age (GA) 26.5 ± 2.1 weeks, birth weight (BW) 913±230 g) had no BPD, 32 infants (GA 25.8±1.4 weeks, BW 768 ± 157 g) developed BPD and 16 infants (GA 24.5 ± 1.1 weeks, BW 710 ± 143 g) died before 36 weeks PMA. Ang2 concentrations were significantly lower in infants with no BPD (median, 25th and 75th percentile) (157, 16 and 218 pg mg À1 ) compared with those who developed BPD (234, 138 and 338 pg mg À1 , P ¼ 0.03) or BPD and/or death (234, 157 and 347 pg mg À1 , P ¼ 0.017), in the first week of life. Twenty-six VPIs (BW 719±136 g, GA 25.1±1.3 weeks) received 27 courses of Dex. Ang2 concentrations before starting Dex were 202, 137 and 278 pg mg À1 and significantly decreased to 144, 0 and 224 pg mg À1 after therapy (P ¼ 0.007).Conclusions: Higher Ang2 concentrations in TAs are associated with the development of BPD or death in VPIs. Dex use suppressed Ang2 concentrations.
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