Reversal Of Inflammation Research Articles

Is pulmonary inflammation a valid predictor of particle induced lung pathology? The case of amorphous and crystalline silicas

Although inflammation is a normal and beneficial response, it is also a key event in the pathology of many chronic diseases, including pulmonary and systemic particle-induced disease. In addition, inflammation is now considered as the key response in standard settings for inhaled particles and a critical endpoint in OECD-based sub-acute/ chronic animal inhalation testing protocols. In this paper, we discuss that whilst the role of inflammation in lung disease is undeniable, it is when inflammation deviates from normal parameters that adversity occurs. We introduce the importance of the time course and in particular, the reversibility of inflammation in the progression towards tissue remodelling and neoplastic changes as commonly seen in rat inhalation studies. For this purpose, we used sub-chronic/ chronic studies studies with synthetic amorphous silicas (SAS) and reactive crystalline silica (RCS) as a source of data to describe the time-course of inflammation towards and beyond adversity. Whilst amorphous silicas induce an acute but reversible inflammatory response, only RCS induces a persistent, progressive response after cessation of exposure, resulting in fibrosis and carcinogenicity in rodents and humans. This suggests that the use of inflammation as a fixed endpoint at the cessation of exposure may not be a reliable predictor of particle-induced lung pathology. We therefore suggest extending the current OECD testing guidelines with a recovery period, that allows inflammation to resolve or progress into altered structure and function, such as fibrosis.

Role of QRS amplitude, fractionation and duration in predicting clinical response to anti-inflammatory treatment in cardiac sarcoidosis

Abstract Background Low QRS amplitude (QRSa), QRS fractionation (QRSf) and longer QRS duration (QRSd) are markers of myocardial fibrosis and inflammation in non-ischemic cardiomyopathy (NICM). Objective To determine if reduction of inflammation with treatment of cardiac sarcoidosis (CS) may reverse these 12 lead ECG parameter changes. Methods 21 patients (pts) with CS and VT ablation with a positive baseline positron emission tomographic (PET 1) scan were studied. All pts received prednisone ≥40 mg for 4 to 8 weeks followed by a taper and maintenance with methotrexate ± low-dose prednisone, <10 mg/day, until clinically stable and resolution of inflammation on PET 2 one year after initial. In addition, pts with low LV ejection fraction (13/21) received guideline directed medical therapy for heart failure. Pts at 1yr with positive PET2 (9) were compared to those with negative PET2 (12). Baseline and 1yr 12-lead ECGs were analyzed for QRSd, ≥2QRSf contiguous leads and QRSa in the limb leads. Results Pts in PET2(+) vs PET2(−) groups has similar gender (men 89% vs 100%, p=0.42), age (57±8 vs 56±10 years, p=0.8) and LV ejection fraction (41±11 vs 46±11, p=0.31). Baseline 12-lead ECGs showed similar QRSd, ≥2QRSf contiguous leads and QRSa for PET2(+) vs PET2(−); P all >0.15 (Table 1). At 1 yr there was a lower prevalence of ≥2QRSf contiguous leads and strong trend for shorter QRS duration and larger QRSa in lead DI if PET2(−) vs PET2(+). 4 pts demonstrated loss of QRSf 2 contiguous leads and/or increase in QRSa in DI by at least 0.15 mV from baseline if PET2(−) and none if PET2(+). Conclusions In pts with CS and VT, reversal of inflammation may result in a greater QRSa and reduction in QRSf. An increase in QRSa in lead 1 by >0.15mV and/or loss of QRSf identifies a clear positive response to treatment and negative PET at 1 year. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Richard T and Angela Clark Innovation Fund in Cardiovascular Medicine, the Mark S Marchlinski EP Research and Education Fund and the Winkelman Family Fund in Cardiovascular Innovation. Table 1

Pharmacodynamics of Aloe vera and acemannan in therapeutic applications for skin, digestion, and immunomodulation.

Scientific studies of Aloe vera have tentatively explained therapeutic claims from a mechanistic perspective. Furthermore, in vitro outcomes demonstrate that the breakage of acemannan chains into smaller fragments enhances biological effects. These fragments can intravenously boost vaccine efficacy or entrain the immune system to attack cancer cells by mannose receptor agonism of macrophage or dendritic cells. With oral consumption, epithelialisation also occurs at injured sites in the small intestine or colon. The main advantage of dietary acemannan is the attenuation of the digestive process, increasing satiety, and slowing the release of sugars from starches. In the colon, acemannan is digested by microbes into short-chain fatty acids that are absorbed and augment the sensation of satiety and confer a host of other health benefits. In topical applications, an acemannan/chitosan combination accelerates the closure of wounds by promoting granular tissue formation, which creates a barrier between macrophages or neutrophils and the wound dressing. This causes M2 polarisation, reversal of inflammation, and acceleration of the re-epithelialisation process. This review summarises and explains the current pharmacodynamic paradigm in the context of acemannan in topical, oral, and intravenous applications. However, due to contradictory results in the literature, further research is required to provide scientific evidence to confirm or nullify these claims.

Modulation of the endogenous Annexin A1 in a cigarette smoke cessation model: Potential therapeutic target in reversing the damage caused by smoking?

BackgroundSmoking cessation may help in the reversal of inflammation and damage caused by smoking. The endogenous annexin A1 (AnxA1) protein has anti-inflammatory effects which instigates the understanding of its role in the attenuation of inflammatory processes caused by smoking. Material and methodsWistar rats were exposed to cigarette smoke for 8 weeks. After the exposure period, one of the groups remained other 8 weeks in the absence of smoke. Animals not exposed to smoke were used as control. Blood, trachea and lungs were obtained for histopathological, immunohistochemical and biochemical analyses. ResultsLoss of cilia of the tracheal lining epithelium was found by smoke exposure, but smoking cessation led to recovery of the tracheal epithelium. Similarly, chronically exposed-to-smoke animals showed increased lymphocytes and macrophages in bronchoalveolar lavage and higher levels of glucose and gamma-GT in their blood. Reduction of lymphocytes, glucose and gamma-GT occurred after smoking cessation. In addition, IL-1β, IL-6, IL-10, TNF-α and MCP-1 levels were elevated by smoke exposure. Smoking cessation significantly reduced the levels of IL-1β, IL-6 and MCP-1 but increased the IL-10 concentration. Numerous mast cells and macrophages were observed in the lung of chronically exposed-to-smoke animals with reduction by smoking cigarette abstinence. AnxA1 increased expression and concomitant NF-κB reduction were found in the smoking cessation group. ConclusionOur results showed that cigarette abstinence promoted partial recovery of the inflammatory process. The attenuation of the inflammatory profile may be associated with the overexpression of AnxA1 protein.

P145 Exploring mucosal function as a clinical endpoint in ulcerative colitis

The standard for assessing disease activity, clinical remission and response to therapy in ulcerative colitis (UC) includes evaluation of patient symptoms and signs as well as endoscopic mucosal status. The ultimate goal is reversal of inflammation and its control, including a normalisation of mucosal function (i.e., ion transport and barrier integrity). Here, we hypothesise that mucosal function is a relevant target-to-treat endpoint. In this exploratory study, we studied the mucosal transport properties and compared them to endoscopy and histology findings in quiescent UC. We obtained sigmoid biopsies during colonoscopy from 33 UC patients (mean age 39, 23–75 years., 18 females) in clinical remission and 17 healthy controls (mean age 46, 20–68 years., 9 females). Remission was defined as total Mayo score ≤2 and no subscore >1. Mucosal transport function was assessed by measuring electrogenic ion transport (short-circuit current, SCC). Biopsies were mounted in Ussing-chambers and exposed to various pharmacological interventions: Sodium absorption inhibitor, phosphordiesterase inhibitor, specific COX-1 inhibitor, specific COX-2 inhibitor, and non-specific COX inhibitor were applied in order to stimulate or inhibit ion secretion and absorption, thereby assessing transport properties (see Table). Histology was assessed using Geboes score. All evaluations were blinded and performed by central reading. Most UC patients, 24 (73%), had an endoscopic Mayo subscore of 0 and the remaining 9 (27%) scored 1. Evaluated by Geboes, 11 (33%) had a score of 0–0.2 (no inflammation/deep remission), 15 (46%) a score of 1.1 (mild inflammation), while the remaining seven (21%) scored 1.2 (moderate inflammation). All controls were with normal endoscopic and histological findings. No difference in basal SCC was observed in UC patients vs. controls. Rofecoxib induced a significant decrease in SCC in UC patients vs. controls (see Table). This difference was not correlated to histology. Finally, no differences were observed between patient groups in responses to amiloride, theophylline, SC-560, or indomethacin. UC-patients in clinical and endoscopic remission demonstrate abnormal mucosal ion secretion related to the COX-2 pathway, without correlation to histology. Whether this abnormality carries an increased risk for early and/or increased severity at relapse is unresolved. We propose to further evaluate functional mucosal remission as a potential target-to-treat endpoint.

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.

Effects of Essential Oils on Telomere Length in Human Cells

Essential oils are used for their reputed health benefits; reversal of inflammation, oxidative damage, and infection are some of the therapeutic effects that essential oils are believed to possess. In many cases, there is scientific evidence to back these claims. However, the purported anti-aging effects of essential oils are not yet supported by the literature. We set out to evaluate the effects of 31 oils on telomere length, believed to play a role in cellular senescence. Cells were subjected to oils in the presence or absence of hydrogen peroxide, and changes in telomere length were measured using a PCR-based assay. Two oils which showed telomere-protective effects were further characterized using a cytogenetic assay, staining for telomeres. Significant variability was seen among these oils with respect to their ability to induce an apparent increase or decrease in telomere length, and to protect against peroxideinduced telomere damage. Expression analysis showed that telomere-protective oils did not increase telomerase (hTERT) gene transcription, but reduced TERF-1, a suppressor of telomere length. Though this mechanism is not yet understood, these data provide a base upon which the community can build, and represent the first formal scientific foray into the study of essential oils on the telomere. Conclusion: Certain essential oils, including those from basil and rosemary, appear to have telomere-protective effects, mediated through a reduction of the TERF-1 telomere-suppressive protein.

ALPHA B-CRYSTALLIN SUPPRESS VENTRICULAR ARRHYTHMIA BY INCREASING CONDUCTION VELOCITY AND ATTENUATING OXIDATIVE STRESS IN RAT AUTOIMMUNE MYOCARDITIS

Myocarditis is a major cause of heart failure and arrhythmia. Despite a lack of direct evidence that inflammation causes ventricular arrhythmia, reversal of inflammation is considered a plausible therapy. This study evaluated whether a small heat shock protein, alpha B-crystallin (CryAB), could

Lupus erythematosus: considerations about clinical, cutaneous and therapeutic aspects.

Systemic Lupus Erythematosus is a chronic inflammatory disease with multifactorial etiology. Although clinical manifestations are varied, the skin is an important target-organ, which contributes to the inclusion of skin lesions in 4 out of the 17 new criteria for the diagnosis of the disease, according to the Systemic Lupus International Collaborating Clinics. The cutaneous manifestations of lupus are pleomorphic. Depending on their clinical characteristics, they can be classified into Acute Cutaneous Lupus Erythematosus, Subacute Cutaneous Lupus Erythematosus, Chronic Cutaneous Lupus Erythematosus and Intermittent Cutaneous Lupus Erythematosus. Treatment is based on preventive measures, reversal of inflammation, prevention of damage to target organs and relief of adverse events due to pharmacological therapy. The most commonly used treatment options are topical, systemic and surgical treatment, as well as phototherapy. The correct handling of the cases depends on a careful evaluation of the morphology of the lesions and the patient's general status, always taking into consideration not only the benefits but also the side effects of each therapeutic proposal.

PReS-FINAL-2073: The usefulness of musculoskeletal ultrasound in monitoring efficacy of intraarticular infliximab therapy in JIA patients

In the past few years the use of musculoskeletal ultrasound (MSUS) in pediatric rheumatology has proven to be better than clinical examination in detecting synovitis. It is a simple, inexpensive, noninvasive and reproducible method that is ideal for pediatric patient. The progress of therapy options has resulted in quick remission, reversal of inflammation and improvement of life quality; especially with introduction of biologic therapy. To our knowledge this a first report in assessing efficacy of IA infliximab in children with juvenile idiopathic arthritis (JIA) by using MSUS.

ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease

This guideline presents recommendations for the diagnosis and management of patients with celiac disease. Celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. There has been a substantial increase in the prevalence of celiac disease over the last 50 years and an increase in the rate of diagnosis in the last 10 years. Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g., diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) and also non-gastrointestinal abnormalities (e.g., abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, and many other protean manifestations). Indeed, many individuals with celiac disease may have no symptoms at all. Celiac disease is usually detected by serologic testing of celiac-specific antibodies. The diagnosis is confirmed by duodenal mucosal biopsies. Both serology and biopsy should be performed on a gluten-containing diet. The treatment for celiac disease is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms should lead to a review of the patient's original diagnosis to exclude alternative diagnoses, a review of the GFD to ensure there is no obvious gluten contamination, and serologic testing to confirm adherence with the GFD. In addition, evaluation for disorders associated with celiac disease that could cause persistent symptoms, such as microscopic colitis, pancreatic exocrine dysfunction, and complications of celiac disease, such as enteropathy-associated lymphoma or refractory celiac disease, should be entertained. Newer therapeutic modalities are being studied in clinical trials, but are not yet approved for use in practice. Given the incomplete response of many patients to a GFD-free diet as well as the difficulty of adherence to the GFD over the long term, development of new effective therapies for symptom control and reversal of inflammation and organ damage are needed. The prevalence of celiac disease is increasing worldwide and many patients with celiac disease remain undiagnosed, highlighting the need for improved strategies in the future for the optimal detection of patients.

Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p<0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

Estrogen Treatment Reverses Heart Failure-Induced Cardiac Fibrosis and Inflammation

Heart failure is generally characterized by increased fibrosis and inflammation, which lead to functional and contractile defects. Recently we discovered that estrogen (E2) therapy can rescue advanced heart failure (HF) induced by pressure overload in mice by restoring left ventricular (LV) pressure and function. Here, we investigate the effects of E2 on reversing the adverse remodeling of the LV occurring during HF. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 μg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with angiotensin II (AngII) in the presence or absence of E2. Quantitative real-time PCR showed that the transcript levels of the pro-fibrotic markers collagen I, TGFβ, fibrosin 1 (FBRS) and lysil oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11for collagen 1, 1.00±0.86 to 4.33±0.59 for TGFβ, 1.00±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. In vitro studies validated our in vivo findings, as E2 also restored AngII-induced upregulation of LOX and TGFβ from 6.87±0.26 in AngII to 2.80±1.5 in AngII+E2 and 3.30±0.25 to 1.59±0.21 in AngII+E2, respectively (values normalized to CTRL). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1.00±0.19 to 1.90±0.09 and 1.00±0.30 to 5.29±0.77 in HF, respectively, and reversed to CTRL levels with E2 therapy. The anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 with E2 treatment. This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

Intralipid for Amniotic Fluid Embolism (AFE)?

In 1998 it was first showed that intravenous Intralipid could prevent or improve resuscitation from cardiovascular collapse by severe bupivacaine overdose in rats. Since then published examples now include toxicities related to verapamil, diltiazem, amlodipine, quetiapine and sertraline, haldoperidol, lamotrigine, olanzapine, propranolol, atenolol, nevibolol, doxepin, dosulepin, imipramine, amitriptyline, glyosphate herbicide, flecainide, venlafaxine, moxidectin, and others. Amniotic fluid embolism (AFE) is a rare but potentially catastrophic obstetric emergency. Despite earlier recognition and aggressive treatment, morbidity and mortality rates remain high. An estimated 5% - 15% of all maternal deaths in Western countries are due to AFE. The pathophysiology of AFE is not completely understood. AFE most commonly occurs during labor, delivery, or the immediate postpartum period. However, it has been reported to occur up to 48 h postpartum. Pulmonary hypertension and right heart strain/failure may be the result of physical amniotic fluid debris in the pulmonary vasculature or, perhaps more likely, result from circulating pulmonary vasoconstrictive mediators. Therapy with Intralipid in male rats resulted in 100% survival and prevented Pulmonary arterial hypertension-induced right ventricular failure by preserving right ventricular pressure and right ventricular ejection fraction and preventing right ventricular hypertrophy and lung remodeling. In preexisting severe Pulmonary arterial hypertension, Intralipid attenu-ated most lung and right ventricular abnormalities. The beneficial effects of Intralipid in Pulmonary arterial hypertension seem to result from the interplay of various factors, among which preservation and/or stimulation of angiogenesis, suppression and/or reversal of inflammation, fibrosis and hypertrophy, in both lung and right ventricular, appear to be major contributors. In conclusion, Intralipid not only prevents the development of Pulmonary arterial hypertension and right ventricular failure but also rescues preexisting severe Pulmonary arterial hypertension. Intralipid treatment is a new treatment for AFE (amniotic fluid embolism) which was never suggested before. Animal studies should be done in order to evaluate this new treatment modality.

Intralipid Prevents and Rescues Fatal Pulmonary Arterial Hypertension and Right Ventricular Failure in Rats

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) hypertrophy and failure. Intralipid (ILP), a source of parenteral nutrition for patients, contains γ-linolenic acid and soy-derived phytoestrogens that are protective for lungs and heart. We, therefore, investigated the therapeutic potential of ILP in preventing and rescuing monocrotaline-induced PAH and RV dysfunction. PAH was induced in male rats with monocrotaline (60 mg/kg). Rats then received daily ILP (1 mL of 20% ILP per day IP) from day 1 to day 30 for prevention protocol or from day 21 to day 30 for rescue protocol. Other monocrotaline-injected rats were left untreated to develop severe PAH by day 21 or RV failure by approximately day 30. Saline or ILP-treated rats served as controls. Significant increase in RV pressure and decrease in RV ejection fraction in the RV failure group resulted in high mortality. Therapy with ILP resulted in 100% survival and prevented PAH-induced RV failure by preserving RV pressure and RV ejection fraction and preventing RV hypertrophy and lung remodeling. In preexisting severe PAH, ILP attenuated most lung and RV abnormalities. The beneficial effects of ILP in PAH seem to result from the interplay of various factors, among which preservation and/or stimulation of angiogenesis, suppression and/or reversal of inflammation, fibrosis and hypertrophy, in both lung and RV, appear to be major contributors. In conclusion, ILP not only prevents the development of PAH and RV failure but also rescues preexisting severe PAH.

Inflammatory mediators in the aqueous humor from patients with uveitis associated with Behçet’s disease and Vogt‐Koyanagi‐Harada disease

Abstract Purpose We studied interphotoreceptor retinoid‐binding protein (IRBP), a dominant autoimmune antigen in the eye. Methods Aqueous humour samples from 28 patients with active uveitis were analysed for immunoglobulin G (IgG) content as a marker for blood‐ocular barrier breakdown and by gelatinase B zymography for the detection of inflammation. The data were correlated with the presence of intact IRBP (approximately 140 kD) as determined by Western blot analysis and with the clinical disease activity. Results Aqueous humour samples from control eyes and eyes with low disease activity showed positive immunoreactivity for intact IRBP. The IRBP signal weakened or disappeared with higher disease activity. Significant positive correlations were observed between disease activity and levels of gelatinase B/matrix metalloproteinase‐9 (MMP‐9) (rs=0.713; P<0.001) and IgG (rs=0.580; P=0.001). Significant negative correlations were found between levels of IRBP and disease activity (rs=‐0.520; P=0.005) and levels of MMP‐9 (rs=‐0.727; P<0.001) and of IgG (rs=‐0.834; P<0.001). Whereas neutrophil elastase converted intact IRBP into an immunoreactive 55 kD peptide in vitro, the conversion by neutrophil degranulates resembled more the in vivo context with a complete degradation of IRBP. Reversal of inflammation with immunosuppressive therapy was accompanied with reappearance of intact IRBP and disappearance of IgG and MMP‐9. Conclusion The analysis of IRBP proteolysis is useful as a biomarker for uveitis and suggests that inhibition of proteinases might become a therapeutic strategy in an inflammatory context of a damaged blood‐ocular barrier.

Interphotoreceptor retinoid‐binding protein as biomarker in systemic autoimmunity with eye inflictions

Autoimmune diseases of the eye, exemplified by Beh cet disease and Vogt-Koyanagi-Harada disease, are a major cause of blindness. We studied interphotoreceptor retinoid-binding protein (IRBP), a dominant autoimmune antigen in the eye. Aqueous humour samples from 28 patients with active uveitis were analysed for immunoglobulin G (IgG) content as a marker for blood-ocular barrier breakdown and by gelatinase B zymography for the detection of inflammation. The data were correlated with the presence of intact IRBP (≈140 kD) as determined by Western blot analysis and with the clinical disease activity. Aqueous humour samples from control eyes and eyes with low disease activity showed positive immunoreactivity for intact IRBP. The IRBP signal weakened or disappeared with higher disease activity. Significant positive correlations were observed between disease activity and levels of gelatinase B/matrix metalloproteinase-9 (MMP-9) (rs= 0.713; P < 0.001) and IgG (rs= 0.580; P= 0.001). Significant negative correlations were found between levels of IRBP and disease activity (rs=−0.520; P= 0.005) and levels of MMP-9 (rs=−0.727; P < 0.001) and of IgG (rs=−0.834; P < 0.001). Whereas neutrophil elastase converted intact IRBP into an immunoreactive 55 kD peptide in vitro, the conversion by neutrophil degranulates resembled more the in vivo context with a complete degradation of IRBP. Reversal of inflammation with immunosuppressive therapy was accompanied with reappearance of intact IRBP and disappearance of IgG and MMP-9. The analysis of IRBP proteolysis is useful as a biomarker for uveitis and suggests that inhibition of proteinases might become a therapeutic strategy in an inflammatory context of a damaged blood-ocular barrier.

Transglutaminase 2 in inflammation

Many reports have shown that the expression of transglutaminase 2 (TG 2) is increased in inflammatory diseases. Although during the last several decades multiple physiological roles for TG 2 have been demonstrated in various cell types, its role in the inflammatory process is not yet clear. TG 2 is a crosslinking enzyme that is widely used in many biological systems for tissue stabilization purposes and immediate defense against injury or infection. Aberrant activation of TG 2 activity in tissues contributes to a variety of diseases including neurodegenerative diseases, autoimmune diseases, and cancers. In most cases, TG 2 appears to form an inappropriate protein aggregate that may be cytotoxic enough to trigger inflammation and/or apoptosis. In some cases, such as celiac disease and rheumatoid arthritis, TG 2 is also associated with the pathogenic progression, as well as in the generation of autoantibodies. Recently, we discovered that increased TG 2 activity triggers NF-kappaB activation without I-kappaBalpha kinase signaling. TG 2 induces the polymerization of I-kappaBalpha rather than stimulating I-kappaBalpha kinase. This polymerization of I-kappaB results in the direct activation of NF-kappaB in various cell lines. We also found that TG inhibition reverses NF-kappaB activation. Interestingly, this coincides with the reversal of inflammation in conjunctivitis models by treatment with TG 2 inhibitors. Here, I introduce a new role for TG 2 as a signal modulator, which may suggest a new paradigm for the inflammatory process.

Assessing the Role of Neutrophil Apoptosis in the Resolution of Particle-Induced Pulmonary Inflammation

Following inflammatory-cell recruitment in the lung, neutrophil apoptosis and subsequent engulfment by macrophages are regarded as important components in the resolution of pulmonary inflammation. The goal of this study was to further investigate the role of apoptosis and its influence, if any, on the pulmonary inflammatory process following exposures to the following particulate types: amorphous (AMO) or crystalline silica (Si), lipopolysaccharide (LPS), or pigment-grade titanium dioxide (TiO 2) . Rats were intratracheally instilled either with TiO 2, AMO, or Si particles at doses of 1 or 5 mg/kg or 6 µg LPS. Following exposures, bronchoalveolar lavage fluids and lung tissues were collected and evaluated at 12, 24, 48, or 168 h (i.e., 1 wk). At the 1 mg/kg dose, AMO instillation produced the highest pulmonary inflammatory response, concomitant with a rise in apoptotic cells that mirrored temporally the transient nature of the inflammatory response. At 5 mg/kg, amorphous silica and crystalline silica particles induced substantial pulmonary inflammation [~50-60% neutrophils (PMNs)] at 12 h postexposure (pe). A fundamental difference between the two inflammatory patterns, however, was the subsequent reversibility of inflammation in the AMO-exposed rats at 168 h postexposure and the sustained inflammatory effect in the Si-exposed animals measured through 168 h pe (~40% PMNs). Pulmonary apoptotic responses in AMO-exposed rats mirrored temporally and correlated with the time-course reduction of inflammatory responses, leading to resolution. In the Si-exposed rats, apoptotic levels remained elevated, concomitant with sustained inflammation measured through 168 h pe. High doses of TiO 2 particles produced transient lung inflammation, but with low levels of apoptosis. In addition, instillation of LPS produced a transient inflammatory response which mirrored the time course of apoptosis levels and was resolved by 168 h pe. cDNA microarray methods demonstrated that gene expression was altered for several apoptosis-related genes in AMO-, Si-, and LPS-exposed animals at 24 h pe. The results of these studies demonstrate that, following exposures, the resolution of lung inflammation correlated temporally with apoptotic levels of neutrophils in AMO- and LPS-exposed rats. Alternatively, instillation of crystalline silica resulted in sustained pulmonary inflammation and measurable apoptosis at 1 wk postexposure, but the apoptotic cell processes were not effective in resolving the inflammatory response. The findings suggest that the coordination between the resolution of inflammation and inflammatory cell apoptosis in the lung is dependent on the particle-type and that other factors, such as particle cytotoxicity, may also be important.

Laughter is the Best Medicine

Quality of life is perceived according to individual conception and is best evaluated by the patient rather than by others. It is the condition of one’s being, reflected in the ability to perform everyday activities, as assessed according to physical, psychological, spiritual, and social dimensions. Among oncology patients, the quality of life is reflected in satisfaction with levels of functioning and control of the symptoms of both disease and treatment. 6