Proinflammatory Cytokines and the Hypermetabolism of Children with Sickle Cell Disease

Abstract

Sickle cell anemia (HbSS) includes chronic inflammation, but the origin is unclear. We hypothesized that in stable HbSS patients the inflammation was associated with hypermetabolism. We compared selected hypermetabolic and key immunomodulator indicators in HbSS versus control children and examined associations between measures of hypermetabolism and inflammation. Twelve fasting asymptomatic HbSS children 6-12 years and 9 controls matched for age, gender and fat mass (FM) were studied. Proportional reticulocyte count (retic%) and resting energy expenditure (REE) represented hypermetabolism, and C-reactive protein (CRP) indicated inflammation. Proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), chemokine monocyte chemoattractant protein-1 (MCP-1), and energy balance cytokine leptin were measured. Methods were indirect calorimetry, enzyme-linked immunosorbent assay, and radioimmunoassay. Statistical analysis included simple correlation and regression analysis. REE (51 ± 6 vs. 43 ± 12 kcal/kg per fat-free mass (FFM), mean ± SD), retic% (12 ± 4 vs. 0.7 ± 0.3%), CRP (5 ± 3 vs. 0.3 ± 0.4 mg/liter), and IL-6 (71 ± 40 vs. 20 ± 7 pg/ml) were significantly higher for HbSS than controls (P < 0.05). Conversely, leptin (0.1 ± 0.1 vs. 2 ± 1 µg/liter per kgFM) and MCP-1 (34 ± 5 vs. 41 ± 4 pg/ml) were significantly lower for the HbSS subjects (P < 0.01). TNF-α was not significantly different. There were no significant associations between REE or retic% and any cytokine measured. However, CRP was significantly associated with REE in HbSS (r = 0.8, P = 0.003) and an important predictor of REE/FFM. We provide new evidence for low circulating levels of inflammatory chemokine MCP-1 in stable HbSS children, confirm mostly low cytokine levels, inflammation, and hypermetabolism and demonstrate association of hypermetabolism with inflammation via CRP but not via cytokines.

Erythropoiesis and Myocardial Energy Requirements Contribute to the Hypermetabolism of Childhood Sickle Cell Anemia

“…Recent understanding of HbSS pathology includes baseline inflammation, which so far is defined mainly by marked leukocytosis linked with disease severity (33). We have shown that in patients with HbSS, C-reactive protein, a sensitive indicator of inflammation, is an important predictor of REE adjusted for FFM (21). It is therefore possible that consideration of inflammatory factors could further increase the precision of predictive equations for REE in HbSS subjects (14).…”

“…Average dietary protein (HbAA, 1.57 ± 0.26 g/kg body weight per day; HbSS, 1.79 ± 0.38 g/kg body weight per day) and energy (HbAA, 51 ± 13 kcal/kg body weight per day; HbSS, 60 ± 16 kcal/kg body weight per day) intakes were not different between the groups. Physical characteristics and hematology for the participants are shown in Table 1 and are described in detail elsewhere (21). There was no significant age difference between the HbSS and HbAA groups.…”

“…Body weight, height and fat mass were measured, as previously described (21). Body mass index (kg/m 2 ) was calculated from weight and height.…”

“…The REE (kilocalories per day) was measured for 30 minutes by indirect calorimetry using a metabolic cart (DeltaTrac; SensorMedics, Yorba Linda, CA) with hood after 12 hours of overnight fast with water (21). Energy expenditure was calculated by the data acquisition system of the metabolic cart using the Weir formula (23).…”

Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia

“…Chemokines and their receptors have been implicated in the development of vascular inflammatory disorders, and, in this regard, higher levels of proinflammatory cytokines and chemokines have been reported to be present in patients with sickle cell disease (4)(5)(6).…”