Steroid-Resistant Neutrophilic Inflammation in a Mouse Model of an Acute Exacerbation of Asthma

Abstract

Neutrophilic inflammation in acute exacerbations of asthma tends to be resistant to treatment with glucocorticoids. This may be related to decreased activity and expression of histone deacetylase-2 (HDAC2), which down-regulates expression of proinflammatory genes via recruitment to the glucocorticoid receptor complex. We assessed airway inflammation and response to steroid treatment in a novel mouse model of an acute exacerbation of chronic asthma. Systemically sensitized mice received low-level challenge with aerosolized ovalbumin for 4 weeks, followed by a single moderate-level challenge to induce enhanced inflammation in distal airways. We assessed the effects of pre-treatment with dexamethasone on the accumulation of inflammatory cells in the airways, airway responsiveness to methacholine, expression and enzymatic activity of nuclear proteins including histone acetyl transferase (HAT) and HDAC2, and levels of transcripts for neutrophil chemoattractant and survival cytokines. Dexamethasone suppressed inflammation associated with eosinophil and T-lymphocyte recruitment, but did not prevent neutrophil accumulation or development of airway hyperresponsiveness. Increased activity of HAT was suppressed by steroid treatment, but the marked diminution of HDAC2 activity and increased activity of nuclear factor-kB were not reversed. Correspondingly, elevated expression of mRNA for TNF-a, granulocytemacrophage colony-stimulating factor, IL-8, and p21 waf were also not suppressed by dexamethasone. Levels of lipid peroxidation and protein nitration products were elevated in the acute exacerbation model. We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity.

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

“…Next, we examined neutrophilic airway inflammation directly in CD4-Cre + Menin fl/fl mice by using a previously reported steroid-resistant neutrophilic airway inflammation model (Fig. 2E) (32). The levels of IL-17A in BAL fluid samples from CD4-Cre + Menin fl/fl mice were dramatically reduced (P < 0.05) in comparison with BAL fluid samples from WT mice (Fig.…”

The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

“…Similar to the lung weights, the spleens of the infected mice weighed more than the spleens of the uninfected (naïve and DMPA treatment only) mice, but no difference was observed in the spleen weights of DMPA-treated C57BL/6 and BALB/c mice compared to untreated mice (data not shown). Histopathological scoring was further done to determine the extent of perivascular, peribronchiolar, and intra-alveolar lymphocytic infiltration, as glucocorticoids are known to differentially alter the accumulation of inflammatory cells in the airways (27). DMPA treatment resulted in significantly decreased inflammation in the peribronchiolar regions 16 weeks postinfection (P ϭ 0.037; Fig.…”

“…Contraceptive doses of DMPA also influenced the recruitment and accumulation of inflammatory cells to and at the site of disease. Glucocorticoid therapies are known to deplete monocyte populations in humans (34) and limit the recruitment of eosinophils and T lymphocytes but not neutrophils in the airways of mice (27). DMPA treatment furthermore resulted in an increased bacterial burden in C57BL/6 mice infected with M. tuberculosis compared to that of untreated mice.…”

Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway

“…Consistent with this concept, dysregulated gene expression has been documented in peripheral blood mononuclear cells and bronchoalveolar lavage cells from corticosteroid-resistant patients with asthma (8)(9)(10). Murine asthma models have also identified corticosteroid-unresponsive genes and the dissociation of airway inflammation from airway hyperreactivity (AHR) and remodeling responses in response to corticosteroid treatment (11)(12)(13). Taken together, these human and murine studies suggest that distinct sets of corticosteroid-unresponsive genes modulate disease severity in severe asthma that is refractory to corticosteroid therapy.…”