Impaired anti-inflammatory action of glucocorticoid in neutrophil from patients with steroid-resistant asthma

Abstract

BackgroundSteroid resistant (SR) asthma is characterized by persistent airway inflammation that fails to resolve despite treatment with high doses of corticosteroids. Furthermore, SR patient airways show increased numbers neutrophils, which are less responsive to glucocorticoid. The present study seeks to determine whether dexamethasone (DEX) has different effect on neutrophils from steroid sensitive (SS) asthmatics compared to SR asthmatics.MethodsAdults with asthma (n = 38) were classified as SR or SS based on changes in lung FEV1% following a one-month inhaled corticosteroid (ICS) treatment. Blood samples were collected from all patients during their first visit of the study. Neutrophils isolated from the blood were cultured with dexamethasone and/or atopic asthmatic serum for 18 h. The mRNA expression of mitogen-activated protein kinase phosphatase-1 (MKP-1), a glucocorticoid transactivation target, and glucocorticoid-induced transcript 1 (GLCCI1), an early marker of glucocorticoid-induced apoptosis whose expression was associated with the response to inhaled glucocorticoids in asthma , was determined by real-time PCR, and ELISA was used to assess the pro-inflammatory cytokine IL-8 levels in the supernatant. Constitutive neutrophil apoptosis was detected by flow cytometry.ResultsDEX significantly induced MKP-1 expression in both patients with SS and SR patients in a concentration-dependent manner, but greater induction was observed for SS patients at a low concentration (10−6 M). Asthmatic serum alone showed no MKP-1expression, and there was impaired induction of MKP-1 by DEX in SR asthma patients. The expression of GLCCI1 was not induced in neutrophils with DEX or DEX/atopic asthmatic serum combination. Greater inhibition of IL-8 production was observed in neutrophils from patients with SS asthma treated with DEX/atopic asthmatic serum combination compared with SR asthma patients, though DEX alone showed the same effect on neutrophils from SS and SR asthma patients. Meanwhile, DEX dependent inhibition of constitutive neutrophil apoptosis was similar between SS asthma and SR asthma patients.ConclusionsDEX exerted different effects on neutrophils from patients with SS asthma and SR asthma, which may contribute to glucocorticoid insensitivity.

Aberrant function of neutrophils in asthma

“…The persistent neutrophilia in asthma should not own to the use of glucocorticoids, because glucocorticoids exerted the same effects on the apoptosis of neutrophils from steroid-sensitive asthma and steroid-resistant asthma with increased neutrophils in airway, as shown in our study [18] . In addition, Uddin and colleagues indicated that unresolved airways neutrophilia in severe asthma were the result of their prolonged survival promoted by factors released by inflammatory and structural cells of the airways [58] .…”

“…This phenomenon could be explained by increased chemotactic factors, such as IL-8, TNFα, LTB4 and IL-17A, in the circulation of patients suffering from asthma [6,[14][15][16][17] . Our previous study also demonstrated that neutrophils from steroid-resistant asthma released more IL-8 at the presence of asthmatics serum, which might contribute to additional recruitment and activation of neutrophils in a positive feedback manner [18] . Moreover, Lavinskiene et al reported that the migration of neutrophils to the airways after allergen challenge was increased in asthmatic comparing to non-asthmatic subjects, because they were more sensitive to IL-8 stimulation [19] .…”

“…Though, Hirsch and colleagues reported that glucocorticoids exerted similar genomic effects on neutrophils and on other blood leukocytes by quantifying the effect of glucocorticoids on LPS-induced pro-inflammatory mRNA expression in neutrophils and neutrophil-depleted leukocytes [98] . In our recent study, dexamethasone exerted impaired anti-inflammatory action on neutrophils from steroid-resistant asthma at the present of atopic asthmatic serum, a mimic of asthmatic milieu, by showing that the inhibition of IL-8 production by dexamethasone in steroid-resistant asthma was less when compared to steroid-sensitive asthma [18] . Similarly, a previous study on blood neutrophils in severe asthma shown that oxidative burst stimulated by phorbol myristate acetate (PMA), and the release of IL-8 which represented the activation of neutrophils, were not inhibited by oral corticosteroids [99] .…”

“…Decreased phagocytosis in neutrophils did not return to normal after corticosteroid treatment [24] , because corticosteroids decrease the phagocytosis which has been seen in monocytes with decreased phagocytosis and repression the release of inflammatory cytokines by corticosteroids [108,109] . Asthmatic milieu impedes the anti-inflammatory of glucocorticoid in steroid resistant asthma [18] . Macrophage migration inhibitory factor (MIF) is an immunologic regulator that has anti-glucocorticoid effects [110] .…”

Obesity affects peripheral lymphoid organs immune response in murine asthma model

“…This profile develops due to an increased neutrophil influx, overcoming the classic asthmatic eosinophilia . It is already established that neutrophils are more resistant to glucocorticoids, contributing to the severity of the disease . Several mechanisms have been associated with this shift, as increased NLRP3 inflammasome activation, DC activation failure, macrophage profile modification and lower TSLP levels …”