Elena Goleva1, Denise C Babineau2, Michelle A Gill3, Leisa P Jackson4, Baomei Shao3, Zheng Hu3, Andrew H Liu4, Cynthia M Visness2, Christine A Sorkness5, Donald Y M Leung4, Alkis Togias6, William W Busse5. 1. Department of Pediatrics, National Jewish Health, Denver, Colo. Electronic address: golevae@njhealth.org. 2. Rho Federal Systems Division, Chapel Hill, NC. 3. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Tex. 4. Department of Pediatrics, National Jewish Health, Denver, Colo. 5. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 6. National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Abstract
BACKGROUND: Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important. OBJECTIVE: We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response. METHODS: PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 μg or more of fluticasone propionate (FLU) with or without a long-acting β-agonist versus 100 μg or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor α and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-α) were measured by using RT-PCR in freshly isolated cells and in response to 10-8 mol/L FLU. RESULTS: Compared with PBMCs from patients with easy-to-control asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor α levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-α suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-α suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroid-mediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-to-control and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively). CONCLUSIONS: PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.
BACKGROUND: Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important. OBJECTIVE: We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response. METHODS: PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 μg or more of fluticasone propionate (FLU) with or without a long-acting β-agonist versus 100 μg or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor α and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-α) were measured by using RT-PCR in freshly isolated cells and in response to 10-8 mol/L FLU. RESULTS: Compared with PBMCs from patients with easy-to-control asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor α levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-α suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-α suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroid-mediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-to-control and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively). CONCLUSIONS: PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.
Authors: Gabriela M Wochnik; Joëlle Rüegg; G Alexander Abel; Ulrike Schmidt; Florian Holsboer; Theo Rein Journal: J Biol Chem Date: 2004-12-09 Impact factor: 5.157
Authors: Stephen J Teach; Michelle A Gill; Alkis Togias; Christine A Sorkness; Samuel J Arbes; Agustin Calatroni; Jeremy J Wildfire; Peter J Gergen; Robyn T Cohen; Jacqueline A Pongracic; Carolyn M Kercsmar; Gurjit K Khurana Hershey; Rebecca S Gruchalla; Andrew H Liu; Edward M Zoratti; Meyer Kattan; Kristine A Grindle; James E Gern; William W Busse; Stanley J Szefler Journal: J Allergy Clin Immunol Date: 2015-10-27 Impact factor: 10.793
Authors: Ann Esquivel; William W Busse; Agustin Calatroni; Alkis G Togias; Kristine G Grindle; Yury A Bochkov; Rebecca S Gruchalla; Meyer Kattan; Carolyn M Kercsmar; G Khurana Hershey; Haejin Kim; Petra Lebeau; Andrew H Liu; Stanley J Szefler; Stephen J Teach; Joseph B West; Jeremy Wildfire; Jaqueline A Pongracic; James E Gern Journal: Am J Respir Crit Care Med Date: 2017-10-15 Impact factor: 21.405
Authors: Elena Goleva; Ling-Bo Li; P Taylor Eves; Matthew J Strand; Richard J Martin; Donald Y M Leung Journal: Am J Respir Crit Care Med Date: 2005-12-30 Impact factor: 21.405