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.

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Social disruption (SDR) is a well-characterized mouse stressor that causes changes in immune cell reactivity in response to inflammatory stimuli. In this study, we found that SDR in the absence of an immune challenge induced pulmonary inflammation and increased pulmonary myeloperoxidase activity. The percentage of neutrophils within the lungs increased 2-fold after social disruption. Monocyte accumulation in the lungs was also significantly increased. In addition, SDR increased the percentage of neutrophils that expressed CD11b, indicating that more neutrophils were in an activated state. In the lungs, we observed an increased level of the inflammatory cytokine, IL-1β, as well as higher levels of KC/CXCL1, MIP2/CXCL2, and MCP-1/CCL2, which are chemokines responsible for neutrophil and monocyte recruitment. Furthermore, social disruption led to increased lung expression of the adhesion molecules P-selectin, E-selectin, and ICAM-1, which localize and recruit immune cells. These data support previous findings of an inflammatory environment induced by SDR. We demonstrate that this effect also occurs in the pulmonary milieu and in the absence of an inflammatory stimulus.

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, a-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-b, 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.Keywords: ets-2; Type I collagen; pulmonary fibrosis; bleomycin; fibroblast Interstitial lung diseases are a broad set of diseases that perturb lung function by affecting the space between endothelial cells of the vascular bed and alveolar epithelial cells. In normal conditions, this interstitial space consists of a minimal amount of matrix, allowing the efficient transport of oxygen and carbon dioxide. The interruption of this normal lung architecture can alter lung function. One set of lung diseases characterized by interstitial matrix deposition, the destruction of alveolar-capillary units, and functional impairment is termed idiopathic interstitial pneumonias (IIPs).The most prevalent form of IIP is idiopathic pulmonary fibrosis (IPF). Despite exhaustive research into underlying mechanisms, patients with IPF have a median survival of 3-5 years after diagnosis (1). From 1992-2003, the mortality rates for patients with IPF significantly increased, despite ongoing investigation into the molecular mechanisms of the disease (2). The only consistent treatment option is lung transplantation, although more than 30% of patients die on the w...

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.