To cite this article: Alkhouri H, Hollins F, Moir LM, Brightling CE, Armour CL, Hughes JM. Human lung mast cells modulate the functions of airway smooth muscle cells in asthma. Allergy 2011; 66: ...1231–1241.
Background: Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction.
Objectives: To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma.
Methods: Freshly isolated human lung mast cells were stimulated with IgE/anti‐IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum‐deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by 3H‐thymidine incorporation and cell counting, and intracellular signalling by phospho‐arrays.
Results: Mast cell 2‐h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24‐h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24‐h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal‐regulated kinase (ERK) and phosphatidylinositol (PI3)‐kinase pathways. However, prostaglandins, thromboxanes, IL‐4 and IL‐13 were not involved in reducing the proliferation.
Conclusions: Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma.
Nonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to ...understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD.
We performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care.
Response rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation SD 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers.
The majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.
Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, ...open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0-4 liver fibrosis.
Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily. Safety assessments were conducted at the start of the study, and patients were seen in the clinic every 3 months until the study sponsor terminated CVC development. Safety endpoints included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, adverse event severity, and clinical laboratory assessments.
A total of 167 patients were enrolled, with a median treatment duration of 33.6 months. Before study termination, 36 patients (21.6%) prematurely discontinued the study. Treatment-related TEAEs were reported in 28 patients (16.8%). The most common treatment-related TEAEs were 4 cases of diarrhea (2.4%) and 2 cases each (1.2%) of abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, hypertriglyceridemia, myalgia, pruritus, and rash. The majority of these treatment-related events were mild in intensity, and none were life-threatening. There were no clinically meaningful changes in hepatic function, chemistry, or liver parameters from baseline to the end of the study.
In this rollover study, CVC 150 mg once daily was well tolerated in patients with NASH and stage 0-4 liver fibrosis. No new safety signals were reported, and these data further support the safety and tolerability of CVC.
Aims. Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion ...was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. Methods. Integrated analyses of pooled data (N = 435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. Results. Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count greater than or equal to50 * 10.sup.9/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect was consistently positive across clinically important disease and Baseline clinical characteristic subgroups, and using alternate Baseline platelet count cohort definitions. Similarly, more avatrombopag-treated patients achieved greater than or equal to50 * 10.sup.9/L platelets with an increase of greater than or equal to20 * 10.sup.9/L from Baseline. The incidence and severity of adverse events were similar between avatrombopag and placebo. Further, safety data demonstrated a low risk for thromboembolic events and hepatotoxicity. Conclusion. These integrated analyses confirmed the superiority of avatrombopag to placebo in reducing platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD scheduled to undergo an invasive procedure, and its tolerable safety profile. Importantly, these data warrant reconsideration of clinical decision making regarding the need to treat thrombocytopenia in patients with CLD. This trial was registered with NCT01972529 and NCT01976104.
The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to ...establish associations between steatosis amount, type, and distribution in a well-characterized group of children with biopsy-proven nonalcoholic fatty liver disease (NAFLD).
One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin-eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0-3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined.
Median patient age was 12 years and median body mass index was 31 kg/m. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3-204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage.
Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.
The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A ...single‐center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post‐transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty‐eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow‐up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow‐up being significant risk factors. Fifty‐three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.
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