Transcription factor ets-2 plays an important role in the pathogenesis of pulmonary fibrosis.

Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α-smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-ß, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.

Airway inflammation in exercise-induced bronchospasm occurring in athletes without asthma.

Exercise-induced bronchospasm (EIB) occurs in athletes with and without asthma. Studies have suggested an inflammatory basis for EIB in asthmatics; however whether inflammation plays a similar role in EIB in athletes without asthma remains unclear. Our objective was to determine whether there is evidence of an inflammatory basis for exercise-induced bronchospasm occurring in non-asthmatic athletes. Ninety-six athletes without asthma from varsity college teams underwent eucapnic voluntary hyperventilation testing. Sputum was induced from subjects with hypertonic saline inhalation post-eucapnic voluntary hyperventilation testing and was analyzed with enzyme-linked immunosorbent assays for IL-5, IL-8, IL-13, cysteinyl-leukotrienes, prostaglandin E2, histamine, leukotriene B4, and thromboxane B2. In addition, inflammatory (neutrophils, lymphocytes, eosinophils, and macrophages) and epithelial cell counts in sputum were recorded. Multivariate regression modeling showed a significant correlation between concentrations of select inflammatory mediators after eucapnic voluntary hyperventilation testing and severity of EIB. Means of the log-transformed concentrations of inflammatory mediators in EIB-positive athletes were significantly higher post-eucapnic voluntary hyperventilation than in EIB-negative athletes. Similar findings were not demonstrated with inflammatory cells. Concentrations of inflammatory mediators are higher in EIB-positive athletes than in EIB-negative athletes without asthma after eucapnic voluntary hyperventilation testing. The severity of EIB in our cohort also is significantly correlated with increased concentrations of select inflammatory mediators suggesting a potential inflammatory basis for EIB in athletes without asthma.

The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis.

The role of inflammation in idiopathic pulmonary fibrosis (IPF) is controversial. If inflammation were critical to the disease process, lung pathology would demonstrate an influx of inflammatory cells, and that the disease would respond to immunosuppression. Neither is true. The classic pathology does not display substantial inflammation, and no modulation of the immune system is effective as treatment. Recent data suggest that the pathophysiology of the disease is more a product of fibroblast dysfunction than of dysregulated inflammation. The role of inflammation in disease pathogenesis comes from pathology from atypical patients, biologic samples procured during exacerbations of the disease, and careful examination of biologic specimens from patients with stable disease. We suggest that inflammation is indeed a critical factor in IPF and propose five potential nontraditional mechanisms for the role of inflammation in the pathogenesis of IPF: the direct inflammatory hypothesis, the matrix hypothesis, the growth factor-receptor hypothesis, the plasticity hypothesis, and the vascular hypothesis. To address these, we review the literature exploring the differences in pathology, prognosis, and clinical course, as well as the role of cytokines, growth factors, and other mediators of inflammation, and last, the role of matrix and vascular supply in patients with IPF.