Steroid resistance in asthma: Mechanisms and treatment options

Adcock, Ian M.; Ford, Paul; Bhavsar, PK; Ahmad, Tehireem; Chung, Kian Fan

doi:10.1007/s11882-008-0028-4

Cited by 90 publications

(68 citation statements)

References 59 publications

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“…The mechanisms underlying this poor suppressive response to corticosteroids in severe asthma are unclear but many have been proposed from in vitro studies in cells [4]. We observed that AMs from patients with severe asthma demonstrated a greater degree of activation of p38 mitogenactivated protein kinase (MAPK) [2].…”

mentioning

confidence: 91%

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar¹,

Khorasani²,

Hew³

et al. 2009

Eur Respir J

103

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Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone.We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs).PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentrationdependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method.

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mentioning

confidence: 91%

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Bhavsar¹,

Khorasani²,

Hew³

et al. 2009

Eur Respir J

103

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show abstract

“…Current asthma therapies (e.g., corticosteroids) are successful in treating allergic inflammation. However, there is a lack of supporting evidence of reversal of airway fibrosis with optimal control of inflammation by corticosteroids (21,22). Moreover, despite widespread use of anti-inflammatory treatments, recalcitrant asthma with airway remodeling is a major, ongoing challenge in asthma management.…”

Section: Discussionmentioning

confidence: 99%

A Plasminogen Activator Inhibitor-1 Inhibitor Reduces Airway Remodeling in a Murine Model of Chronic Asthma

Lee¹,

Eren

Vaughan

et al. 2012

Am J Respir Cell Mol Biol

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We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma.Keywords: asthma; airway remodeling; collagen deposition; plasminogen activator inhibitor-1; tiplaxtinin Allergic asthma is now the most common chronic disease of children, and one of the most common respiratory diseases in adults. The hallmark of asthma is chronic airway inflammation with multiple pulmonary pathologies, including airway hyperresponsiveness (AHR), eosinophilic infiltration, mucus hypersecretion, and subepithelial fibrosis (1, 2).Plasminogen activator inhibitor (PAI)-1 is a member of the serine protease inhibitor gene family, and the major physiologic inhibitor of the serine proteases, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Because uPA and tPA play important roles in damping tissue matrix deposition, high levels of PAI-1 lead to excess extracellular matrix formation (3). Under normal conditions, PAI-1 is present in plasma and tissues at low concentrations. Elevated levels of PAI-1 are often observed in a variety of pathologic conditions and clinical settings, such as infection, stroke, myocardial infarction, diabetes, obesity, sepsis, and cancers (4, 5). We previously reported that the levels of PAI-1 were elevated in the airways of a murine model of chronic asthma, and that PAI-1 deficiency was associated with reduced airway fibrosis in these mice (6). We also demonstrated that PAI-1 expression wa...

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“…The smoke model is of particular interest because, like human COPD, it is steroidresistant. Steroid resistance is the result of several alterations within the cell, including dysregulation of the glucocorticoid receptor, attenuated histone deacetylase activity, and increased proinflammatory gene transcription (Adcock et al, 2008). The demonstration that aerosolized TG100-115 provides efficacy as an interventional therapy in a smoke-induced neutrophilia model therefore suggests the potential use of TG100-115, not only for patients with COPD but also for steroid-resistant patients with severe asthma (Adcock et al, 2008).…”

Section: E Airway Disordersmentioning

confidence: 99%

Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

Foster

Blunt

Carter

et al. 2012

Pharmacological Reviews

108

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Steroid resistance in asthma: Mechanisms and treatment options

Cited by 90 publications

References 59 publications

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma

A Plasminogen Activator Inhibitor-1 Inhibitor Reduces Airway Remodeling in a Murine Model of Chronic Asthma

Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

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