Essential role for proteinase-activated receptor-2 in arthritis

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis

The Expression and Regulation of Chemokines (CXCL9, CXCL10, CXCL11) in Urinary Bladder Inflammation of the Mouse

Interstitial cystitis is a serious chronic condition that causes bladder pain and increased voiding frequency in millions of adults in the US, most of them women. A possible biomarker that may be linked to bladder inflammation is the CXCL chemokine family, specifically CXCL9, CXCL10, and CXCL11. The goal of this project is to investigate the expression and regulation of these CXCL chemokines during acute and chronic inflammation of the urinary bladder. Wild-type C57BL/6J mice were injected with cyclophosphamide (CYP) to induce bladder inflammation. RT-PCR and ELISAs were used to determine mRNA and protein expression of CXCL9, CXCL10, and CXCL11 chemokines. During CYP-induced cystitis, the detrusor muscle exhibited more CXCL mRNA regulation in both males and females compared to the urothelium. CYP-induced cystitis significantly (p ≤ 0.05) upregulated CXCL10, while CXCL9 and CXCL11 were significantly (p ≤ 0.05) downregulated. CXCL chemokines were also more regulated during acute and intermediate inflammation versus chronic inflammation. Females had significantly (p ≤ 0.05) decreased CXCL9 and CXCL11 protein levels after chronic inflammation. There were no statistical differences between CXCL chemokine protein levels in males. Future research such as immunohistochemistry to focus on tissue distribution of chemokines and use of chemokine receptor antagonist should be performed to further explore the functional role of these chemokines in male and female urinary bladders

N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation

Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body’s natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation

The role of inflammation in age-related disease.

The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation inAge-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified

Occlusion of retinal capillaries caused by glial cell proliferation in chronic ocular inflammation

The inner blood-retinal barrier is a gliovascular unit in which glial cells surround capillary endothelial cells and regulate retinal capillaries by paracrine interactions. During chronic ocular inflammation, microvascular complications can give rise to vascular proliferative lesions, which compromise visual acuity. This pathologic remodelling caused by proliferating Müller cells determines occlusion of retinal capillaries. The aim of the present study was to identify qualitative and quantitative alterations in the retinal capillaries in patients with post-traumatic chronic ocular inflammation or post-thrombotic vascular glaucoma. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in retinal inflammation. Our electron microscopy findings demonstrated that during chronic ocular inflammation, thickening of the basement membrane, loss of pericytes and endothelial cells and proliferation of Müller cells occur with irreversible occlusion of retinal capillaries. Angiogenesis takes place as part of a regenerative reaction that results in fibrosis. We believe that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in the treatment of this disease although further studies are required to confirm these findings

Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk.

Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting

One special question to start with: can HIF/NFkB be a target in inflammation?

Hypoxia and Inflammation are strictly interconnected with important consequences at clinical and therapeutic level. While cell and tissue damage due to acute hypoxia mostly leads to cell necrosis, in chronic hypoxia, cells that are located closer to vessels are able to survive adapting their phenotype through the expression of a number of genes, including proinflammatory receptors for alarmins. These receptors are activated by alarmins released by necrotic cells and generate signals for master transcription factors such as NFkB, AP1, etc. which control hundreds of genes for innate immunity and damage repair. Clinical consequences of chronic inflammatory reparative response activation include cell and tissue remodeling, damage in the primary site and, the systemic involvement of distant organs and tissues. Thus every time a tissue environment becomes stably hypoxic, inflammation can be activated followed by chronic damage and cell death or repair with vessel proliferation and fibrosis. This pathway can occur in cancer, myocardial infarction and stroke, diabetes, obesity, neurodegenerative diseases, chronic and autoimmune diseases and age-related diseases. Interestingly, proinflammatory gene expression can be observed earlier in hypoxic tissue cells and, in addition, in activated resident or recruited leukocytes. Herewith, the reciprocal relationships between hypoxia and inflammation will be shortly reviewed to underline the possible therapeutic targets to control hypoxia-related inflammation in a number of epidemiologically important human diseases and conditions

Bronchoscopic evaluation and final diagnosis in patients with chronic non productive cough with normal Chest X ray

When a proper detailed history, clinical examination, chest X ray and sputum analysis does not yield a definite diagnosis for the cause of chronic cough, bronchoscopy is indicated. We did a descriptive study among 39 patients who underwent bronchoscopic evaluation for chronic cough (more than 4 weeks) with normal chest X ray and without a prior definitive diagnosis. 16 out of 39 patients were diagnosed to have tuberculosis on analysis of the bronchial washings. 6 patients (66.67%) with left upper lobe mucosal inflammation were AFB smear positive. 5 patients ( 31.25 %) with normal bronchoscopy were AFB smear positive.4 out of 5 patients (80 %) with bilateral upper lobe mucosal inflammation were AFB smear positive. Pulmonary tuberculosis can present with chronic non productive cough and normal chest X ray. Bronchoscopy is helpful in establishing the diagnosis. When bronchoscopy shows bilateral or unilateral upper lobe bronchial mucosal inflammation, possibility of tuberculosis is high. Bronchoscopy can be normal in some patients with pulmonary tuberculosis with normal chest x ray and chronic non productive cough. The key message is that early pulmonary tuberculosis can present with chronic non productive cough and normal chest X ray without any other symptoms suggestive of tuberculosis. Bronchoscopy is helpful in establishing the diagnosi

Acute and Chronic Effects of Smoking on Inflammation Markers in Exhaled Breath Condensate in Current Smokers

Background: Long-term cigarette smoking is associated with pulmonary inflammation, but the acute effects of smoking have been less well studied. Analysis of the exhaled breath condensate (EBC) can provide noninvasive markers that might be indicative of inflammation. Objectives: The aim of the study was to determine whether the pH, electrical conductivity and the levels of ammonium and interleukin 8 (IL-8) of EBC were altered in smokers and whether they changed after smoking a single cigarette. Methods: We included 19 healthy nonsmokers (controls), 29 asymptomatic smokers, 10 patients with stable chronic obstructive pulmonary disease (COPD) {[}Global Initiative for Chronic Obstructive Lung Disease stages (GOLD) stages II-III], and 10 patients with exacerbated COPD. In 13 smokers, EBC was also analyzed before and after smoking. EBC was obtained during 10 min tidal breathing with a cooled RTube (TM). pH was determined after deaeration with argon. Results: Acute smoking did not alter the pH or ammonium and IL-8 levels, but raised conductivity. As in COPD patients, the pH was significantly decreased in chronic smokers with a history of at least 10 pack-years compared to controls. Conclusions: EBC can be used to detect the acute and chronic effects of smoking. The increased conductivity of EBC after smoking suggests acute inflammatory effects. The reduced pH in chronic smokers shows cigarette-induced inflammation. Copyright (C) 2009 S. Karger AG, Base