HELLP syndrome is associated with an increased inflammatory response. Circulating IL-6 levels in HELLP syndrome are reduced during prednisolone administration, suggesting a stabilizing effect on the inflammatory endothelial process.
Aim
Increased end-tidal carbon monoxide (ETCOc) and cytokines in preterm infants are related to bronchopulmonary dysplasia and intraventricular haemorrhages. The aim was to study the predictive value of ETCOc and cytokine levels for long-term outcome.
Methods
This study comprised 105 very preterm infants (57 males, 48 females; gestational age range 25wk 5d–31wk 4d; birthweight 610–2100g) who were admitted to a neonatal intensive care unit between 1 February and 31 December 2002. ETCOc, plasma tumour necrosis factor alpha (TNF-α) and interleukins (IL) 6 and 8, and malondialdehyde (MDA, a marker of lipid peroxidation), were measured at days 1, 3, and 5 of life and related to outcome at 3 years 6 months of age (Griffiths Mental Developmental Scales).
Results
Of the 105 infants, 69 were eligible for follow-up (37 male; 32 female; bronchopulmonary dysplasia, n=12). ETCOc at 0 to 24 hours was higher in infants with adverse outcome (Griffiths developmental quotient <85, n=15) compared with favourable outcome (2.7 SD 0.7 vs 2.0 SD 0.5; p<0.05). MDA and cytokines did not differ between groups. Regression analysis with bootstrapping of independent variables (gestational age, birthweight, ETCOc, TNF-α, IL-6, IL-8, and bronchopulmonary dysplasia) showed that ETCOc was the only parameter that correlated with outcome. The sensitivity and negative predictive value of ETCOc for adverse outcome were 93% and 85% respectively.
Interpretation
Adverse neurodevelopmental outcome is associated with increased endogenous carbon monoxide. ETCOc less than 2.0ppm during the first day indicates a favourable outcome.
Background
Chronic pain is a major problem in many diseases, including RA and OA, arising from inflammation or structural damage. It is often associated with glial cell-mediated inflammatory responses in the spinal cord leading to enhanced pain perception (hyperalgesia), which is difficult to treat. Moreover, therapeutic options are limited. Despite the potential of IL4 and IL10 to inhibit inflammation and pain in experimental models, clinical studies were disappointing, likely due to poor bioavailability. We developed a novel option to inhibit multiple inflammatory responses by constructing an IL4/IL10 fusion protein (IL4-10 synerkine). This synerkine is a novel biologic that combines the distinct characteristics of IL4 and IL10, with an increased mass and anticipated improved bioavailability. Strong anti-inflammatory potential of the synerkine was demonstrated in human in vitro assays.
Objectives
To investigate the capacity of IL4-10 synerkine to treat chronic pain induced by inflammation or nerve damage.
Methods
IL4-10 synerkine, injected intrathecally (it), was tested in 3 mouse models of chronic pain. First, chronic inflammatory hyperalgesia was induced by intraplantar injection of carrageenan. Secondly, we used mice with a cell-specific reduction of ~50% in GRK2 level in microglia/macrophages (LysM-GRK2+/- mice) that develop persistent inflammatory hyperalgesia after a single intraplantar injection of IL-1b, while WT mice develop a transient hyperalgesia. Thirdly, chronic neuropathic pain was induced by spared nerve injury (SNI). Hyperalgesia was assessed by Hargreaves test to determine heat withdrawal latencies and Von Frey hairs to determine mechanical thresholds. To demonstrate surplus value of the synerkine, IL-4 and IL-10 mono and combination therapies were tested.
Results
Intraplantar injection of carrageen induced profound persistent hyperalgesia in WT mice. A single it. injection of IL4-10 synerkine completely inhibited established carrageenan-induced persistent hyperalgesia (for 40, 100 and 200 ng all p<0.001) for at least 2 days. The highest dose of IL4-10 synerkine significantly inhibited hyperalgesia for 4 days (p<0.05). Injection of IL4, IL10, or a combination (100 ng) only modestly inhibited hyperalgesia (30-40%) for 1 day. It. administration of IL4-10 synerkine also dose-dependently inhibited IL-1β-induced persistent hyperalgesia in LYSM-GRK2+/- mice. Single injections of 100 ng and higher, completely prevented the development of IL-1β-induced hyperalgesia in LYSM-GRK2+/- mice (p<0.001). Moreover, it shortened the duration of transient IL-1β-induced hyperalgesia in WT mice. Interestingly, IL4-10 synerkine also inhibited mechanical hypersensitivity in the SNI neuropathic pain model, although for shorter time periods (6 hours).
Conclusions
IL4-10 synerkine, next to its strong anti-inflammatory properties, also robustly relieves hyperalgesia in models for inflammatory and neuropathic pain, superior to IL4 or IL10 mono or combination therapy. These data underscore the potential of IL4-10 syne...
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