Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound

Vachier, Isabelle; Bonnans, Caroline; Chavis, C.; Farce, Martine; Godard, P.; Bousquet, Jean; Chanez, Pascal

doi:10.1016/j.jaci.2004.09.038

Cited by 141 publications

(140 citation statements)

References 38 publications

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“…Thus, in severe asthma, it is conceivable that some of the pathobiology is related to a lack of resolution. In this regard, severe asthma has been associated with lower levels of lipoxins, with their potential anti-inflammatory qualities, than in patients with milder asthma [100][101][102].…”

Section: Activation Of Innate Immune Pathwaysmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Activation Of Innate Immune Pathwaysmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…Reduced levels of LX have also been found in the airways of patients suffering from cystic fibrosis and appear to play a role in the disease pathophysiology (24,29,51). LXA 4 receptor expression is induced in vivo in a murine model of airway inflammation, and ALX-transgenic mice are protected from the development of acute inflammation with markedly decreased eosinophil activation and tissue accumulation (52,53).…”

Section: Discussionmentioning

confidence: 99%

“…Changes in LX production can drive the evolution of several diseases such as asthma, fibrosis, cancer, and atherosclerosis (23). Interestingly, diminished levels of LXA 4 are detected in the induced sputum of patients with severe asthma that is characterized by irreversible airway remodeling, including increased collagen deposition and smooth muscle proliferation in the bronchial wall (24).…”

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confidence: 99%

ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis

Martins¹,

Farias-Filho

Molinaro³

et al. 2009

The Journal of Immunology

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Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (α-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-β level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.

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“…In addition epithelial IL-8 was observed in patients with steroid-refractory asthma. IL-8 was more abundant in induced sputum of patients with severe asthma compared to control subjects (Hamilton et al, 2003;Vachier et al, 2005).…”

Section: Introductionmentioning

confidence: 84%

Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

Kim

Lavender

et al. 2009

Exp Mol Med

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Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)β, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRα. However, recent data suggest that GRβ is not a dominant negative inhibitor of GRα in the transrepressive process and has its own functional role. We investigated the functional role of GRβ expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-α-induced IL-8 release in an airway epithelial cell line. GRβ expression was induced by treatment of epithelial cells with either dexamethasone or TNF-α. GRβ was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-α-induced IL-8 transcription was not affected by GRβ overexpression, rather GRβ had its own weak suppressive activity on TNF-α-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRβ overexpression, but TNF-α-induced histone H4 acetylation at the IL-8 promoter was decreased with GRβ overexpression. This study suggests that GRβ overexpression does not affect glucocorticoid-induced suppression of IL-8 expression in airway epithelial cells and GRβ induces its own histone deacetylase activity around IL-8 promoter site.

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Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound

Cited by 141 publications

References 38 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis

Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

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