Corticosteroid Resistant (CR) Asthma Is Associated with Classical Activation Of Airway Macrophages and Exposure To Lipopolysaccharide (LPS)

Hauk, Pia J.; Goleva, Elena; Liu, A.H.; Hall, Clifton F.; Riches, David W. H.; Martin, Richard J.; Leung, Donald Y.M.

doi:10.1016/j.jaci.2005.12.767

Cited by 4 publications

(4 citation statements)

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“…However, emerging data suggest that there is potential for an interrelationship between inflammation in obesity and glucocorticoid insensitivity in that production of proinflammatory cytokines seen in obesity (TNFα, IL6) are upregulated in lung macrophages from individuals with glucocorticoid-insensitive asthma,60 suggesting that the cytokine environment described in obesity may modify the therapeutic response to glucocorticoids. Two post hoc analyses of clinical trial data support this.…”

Section: Effect Of Obesity On Asthma Severity and Response To Treatmentmentioning

confidence: 99%

Obesity and the lung: 4 {middle dot} Obesity and asthma

Sin

Sutherland

2008

Thorax

138

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Over the past 30 years there has been an epidemic of both obesity and asthma in the western world. A large body of robust epidemiological data has linked obesity with the development and severity of asthma in both children and adults and weight reduction with improvements in asthma severity and symptoms. However, it remains unsettled whether this relationship is causal or confounded by some other factor(s) as mechanistic and physiological studies have produced heterogeneous and at times conflicting findings. This review examines the clinical and epidemiological relationship between obesity and asthma and the purported mechanisms that may link these two processes together.

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Section: Effect Of Obesity On Asthma Severity and Response To Treatmentmentioning

confidence: 99%

Obesity and the lung: 4 {middle dot} Obesity and asthma

Sin

Sutherland

2008

Thorax

138

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“…Nonetheless, some evidence of M1 programming of airway macrophages 18 and, to a limited extent, monocytes 20 has been described in patients with severe steroid-resistant asthma and, in turn, associated with reduced MKP-1 induction. 70 Thus it is possible that the reduced MKP-1 induction and low GCRα expression observed herein can be considered a functional readout reflective of disproportionate M1 programming, explaining significant correlation between these markers of glucocorticoids response and impaired efferocytosis by airway macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…3,16,17 Similarly, in patients with severe or glucocorticoid-insensitive asthma, M1 skewing of blood monocytes and alveolar macrophages has been documented. 18–20 These links suggest a possible intersection of obesity and asthma at the level of airway macrophage activation and function. So-called “alternatively activated” or M2 macrophages help to control and resolve inflammation, in part through the recognition and removal of dying cells in a unique phagocytic process called efferocytosis.…”

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confidence: 99%

Obesity impairs apoptotic cell clearance in asthma

Fernandez-Boyanapalli

Goleva

Kolakowski

et al. 2013

Journal of Allergy and Clinical Immunology

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Background Asthma in obese adults is typically more severe and less responsive to glucocorticoids than asthma in nonobese adults. Objective We sought to determine whether the clearance of apoptotic inflammatory cells (efferocytosis) by airway macrophages was associated with altered inflammation and reduced glucocorticoid sensitivity in obese asthmatic patients. Methods We investigated the relationship of efferocytosis by airway (induced sputum) macrophages and blood monocytes to markers of monocyte programming, in vitro glucocorticoid response, and systemic oxidative stress in a cohort of adults with persistent asthma. Results Efferocytosis by airway macrophages was assessed in obese (n = 14) and nonobese (n = 19) asthmatic patients. Efferocytosis by macrophages was 40% lower in obese than nonobese subjects, with a mean efferocytic index of 1.77 (SD, 1.07) versus 3.00 (SD, 1.25; P < .01). A similar reduction of efferocytic function was observed in blood monocytes of obese participants. In these monocytes there was also a relative decrease in expression of markers of alternative (M2) programming associated with efferocytosis, including peroxisome proliferator-activated receptor δ and CX3 chemokine receptor 1. Macrophage efferocytic index was significantly correlated with dexamethasone-induced mitogen-activated protein kinase phosphatase 1 expression (ρ = 0.46, P < .02) and baseline glucocorticoid receptor α expression (ρ = 0.44, P < .02) in PBMCs. Plasma 4-hydroxynonenal levels were increased in obese asthmatic patients at 0.33 ng/mL (SD, 0.15 ng/mL) versus 0.16 ng/mL (SD, 0.08 ng/mL) in nonobese patients (P = .006) and was inversely correlated with macrophage efferocytic index (ρ = −0.67, P = .02). Conclusions Asthma in obese adults is associated with impaired macrophage/monocyte efferocytosis. Impairment of this anti-inflammatory process is associated with altered monocyte/macrophage programming, reduced glucocorticoid responsiveness, and systemic oxidative stress.

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“…Many of the cytokines and other mediators found to be elevated in obesity-related systemic inflammation (such as leptin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein) have also been reported to mediate the development of glucocorticoid resistance in asthma [74]. Emerging clinical data suggest that there is potential for an interrelationship between obesity-related systemic inflammation and glucocorticoid resistance, in that TNF-α and IL-6 have been reported to be upregulated in lung macrophages from glucocorticoid-resistant asthmatics [39], suggesting that the cytokine environment described in obesity may modify therapeutic response to GCs. In this regard, two recent reports [15,52] indicate that overweight and obese patients with asthma may not respond as well as their lean counterparts to inhaled GCs, the most effective asthma controller therapy [2,30].…”

Section: Obesity As a Modifier Of Therapeutic Response In Asthmamentioning

confidence: 99%

Obesity and Asthma

Sutherland

2008

Immunology and Allergy Clinics of North America

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Over the last two decades, the convergence of secular trends indicating increases in the prevalence of obesity and asthma has led to a hypothesis that these two disorders might be related. Although the mechanisms underlying a putative relationship between obesity and asthma have not been fully described, a relatively mature body of literature suggests that obesity increases the risk of incident asthma. This article addresses studies that could be interpreted as supporting the hypothesis that obesity leads to asthma. We evaluate animal studies that provide biological underpinnings to an association between the two disorders and clinical and epidemiologic studies that suggest that the relationship between these two disorders is clinically important.

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Corticosteroid Resistant (CR) Asthma Is Associated with Classical Activation Of Airway Macrophages and Exposure To Lipopolysaccharide (LPS)

Cited by 4 publications

References 0 publications

Obesity and the lung: 4 {middle dot} Obesity and asthma

Obesity and the lung: 4 {middle dot} Obesity and asthma

Obesity impairs apoptotic cell clearance in asthma

Obesity and Asthma

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