Inflammation & Allergy-Drug Targets (Discontinued) - Volume 8, Issue 4, 2009

Background: We have investigated variations in the C-reactive protein levels in groups of patients with left ventricular dysfunction of various causes. Materials and Methods: We have studied 59 patients (ranging from 40 to 80 years, mean age of 64, SD 9) with left ventricular dysfunction caused by dilated cardiomyopathy, valvular heart disease, chronic ischemic cardiomyopathy. These patients have been compared to 30 healthy subjects and to 15 others with acute myocardial infarction. The Creactive protein levels have been analyzed and correlated to echocardiographic index of the left ventricular function as well as to the clinical parameters. Results: the levels of C-reactive protein show a statistically significant difference between healthy controls and patients with chronic left ventricular dysfunction (0.95mg/l +-0.9 vs 10.17+-13.77; p <0.0001); a statistically significant difference between patients with chronic left ventricular dysfunction and patients with acute myocardial infarction (10.17mg/l+-13.7 vs 30.78&[plus;-22.53, p<0.0001), and a statistically significant difference between the group of patients with chronic left ventricular dysfunction of both ischemic and non ischemic origin (15.39mg/l +-18.19 vs 6.83+-8.77, p = 0.0095). When all chronic patients were analyzed together, the levels of C-reactive protein correlated with the New York Heart Association class (r = 0.282, p = 0.015), age (r = 0.231, p = 0.039) and with the end diastolic volume of left ventricle (r = - 0.230, p = 0.040). Conclusions: as shown by increment of C-reactive protein values, the immune system is activated in patients with the chronic left ventricular dysfunction. The patients with the chronic left ventricular dysfunction of an ishemic origin have higher levels of C-reactive protein than those of a non-ischemic origin. This difference could depend on the atherosclerotic process present presumably only in the first group.

Purpose: Renal injury caused by ischemia-reperfusion (IR) can lead to acute renal failure or delayed graft function. Renal ischemia-reperfusion (RIR) induces inflammatory disorders via activation of arachidonic acid metabolism into prostaglandin E2 (PGE2). Two inducible enzymes, COX-2 and microsomal prostaglandin E synthase (mPGES), regulate PGE2 production. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated during cellular stress. Overexpression of HO-1 is beneficial in transplantation models including antigen-independent IR injury, acute and chronic allograft rejection. Materials and Methods: We investigated the effect of HO-1 induction on the COX pathway, antioxidant enzyme activities, malondialdehyde (MDA) levels, and apoptosis in rat kidneys subjected to 45 min ischemia and 1 h or 24 h reperfusion. Rats were injected intraperitoneally with either: 50 mg/kg hemin (HO-1 inducer groups: H1, H2); 50 μmol/kg ZnPP (HO-1 inhibitor groups: Hz1, Hz2); or 0.9% saline (control groups: r1, r2). Sham animals (Sh) did not undergo RIR. Results: Serum creatinine increased significantly after RIR (r vs Sh; p <0.05). Hemin treatment induced a significant decrease in serum creatinine after RIR (H vs r; p <0.05) whereas ZnPP treatment significantly increased serum creatinine levels (Sh vs Hz; p <0.05). Hemin reduced the severity of acute tubular necrosis and significantly reduced COX-2 and mPGES expression (p <0.05). Hemin did not alter depleted antioxidant enzyme activity but did decrease levels of MDA (p <0.05). Hemin also reduced caspase-3 expression. Conclusions: HO-1 decreased the degree and severity of tubular damage after IR, probably by attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.

Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to develop the role of corticosteroid-saving agents. These can be organized in four other steps: Cyclosporine and Methotrexate in a second one; Azathioprine, Mycophenolate Mofetil and Tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a theoretical last one with Cyclophosphamide and Chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non infectious posterior uveitis.

Nervous and immune system interact through many different messenger substances such as neurotransmitters, cytokines or neuropeptides. For instance, neuropeptides are capable of affecting the metabolism of cells belonging to the immune system. Conversely, cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-α and IFN-γ, contribute to the receptor resistance of neuropeptides, reduce the availibility of amino acids which are needed for the synthesis of neurotransmitters or show neurotoxic effects. Other cytokines like granulocyte-colony stimulating factor (G-CSF) may be highly attractive candidates for the treatment of neurodegenerative conditions. Cytokines are decisively involved in the pathophysiology of psychiatric disorders such as depression, schizophrenia or anorexia nervosa as well as in neurological, respectively neurodegenerative diseases like Parkinson's or Alzheimer's. This connection between the immune system and the pathogenesis of psychiatric disorders leads to the concept that immunomodulatory drugs which are already in use for various diseases related to the immune system may also be efficient in the treatment of psychiatric disorders. This article is supposed to give an overview over the current concepts and possibilities since hopefully these hypotheses lead to new therapeutical strategies for psychiatric patients in the future.

Microglia has been demonstrated to play critical roles in various neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) as well as neuroinflammatory disorders including AIDS encephalitis, multiple sclerosis. In this manuscript, we review the possible roles of microglial cells in animal models of these clinical disorders and human clinical cases. Activated microglia has been demonstrated in various brain regions, such as the hippocampus, substantia nigra and cortex in PD, AD and HD. The contribution of microglial cells to these neurodegenerative disorders is supported by findings in animal experiments: (1) microglial activation precedes the neurodegenerative changes; (2) activated microglia surround the region that undergo neurodegeneration and phagocytose the degenerating cells; (3) activated microglia release neurotoxic molecules such as interleukin(IL)-1β, IL-6, TNF-α, nitric oxide, reactive oxygen species; (4) inhibition of microglial activation leads to the amelioration of neurodegeneration, (5) microglia derived from aged animal exert more toxicity to neurons in an age-dependent fashion, in the same way neurodegenerative disorders occur. Although roles of activated microglia in those clinical disorders needs to be further investigated, these findings suggest that microglial cells may contribute to the progression of neurodegenerative changes as well as inflammation in the brain. Thus, the treatment to target microglial inhibition may help to develop the pharmaceutical approaches for those clinical disorders.

Leptin is an adipokine that modulates multiple functions including energy homeostasis, thermoregulation, bone metabolism, endocrine and pro-inflammatory immune responses. Several studies have implicated leptin in the pathogenesis of chronic autoimmune inflammatory conditions such as autoimmune encephalomyelitis, intestinal bowel inflammation and type-1 diabetes. This review focuses on the role of leptin in non-autoimmune inflammatory diseases that include renal, liver and lung inflammation, atherosclerosis and metabolic syndrome, Behcet's disease and endometriosis.

Avoiding oxidative stress in the airways is important for the treatment of respiratory disease associated with gastroesophageal reflux disease (GERD). It is often difficult to decide whether GERD is causing airway inflammation or whether an airway disease is complicated by GERD. Measurement of exhaled breath condensate (EBC) is performed by cooling and collecting the airway lining fluid contained in exhaled air. A decrease of pH and an increase of the 8- isoprostane concentration in EBC have been observed in patients with mild to moderate asthma accompanied by GERD. There are still problems to be overcome before EBC can be used clinically, but pH and 8-isoprostane may be promising objective markers of airway inflammation due to GERD. The disease concept and diagnosis of GERD are constantly advancing, including the development of impedance methods. It is expected that treatment will be based on the latest diagnostic knowledge of GERD associated with respiratory disease and on monitoring of airway inflammation.

New drugs and new approaches of the treatment of chronic obstructive pulmonary disease (COPD) are needed. Despite recent advances in medical therapeutics, treatment of patients with COPD remains largely symptomatic. Although inhaled corticosteroids are currently the drug of choice for anti-inflammatory therapy, the inflammatory process in COPD is essentially steroid resistant. By now, COPD has been increasingly recognized as an inflammatory disease characterized by sputum neutrophilia and, in some cases, eosinophilia. Moreover other cell types thought to play the predominant role in COPD, are cytotoxic T lymphocytes (CD8+ T) cells and machrophages. Leukotriene B4, (LTB 4), a neutrophil and T cell chemoattractant which is produced by machrophages, neurophils and epithelial cells, is a potent inflammatory mediator. Also cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are known to induce mucus secretion, inflammatory cell infiltration, increase vascular permeability and tissue edema, damage ciliary clirens, and cause severe bronchoconstriction. These are derivatives of arachidonic acid, metabolized via 5-lypoxygenase (5-LO) pathway. There are several sites along this pathway that antileukotriene agents exert their action and at the end-organ receptors. They are classified into two major categories: receptor antagonists and synthesis inhibitors. Beneficial effects on therapy of patients with COPD have already derived from studies, while they seem well tolerated. More studies are underway.

Although chronic liver disease has many etiologies, including chronic viral hepatitis, alcohol abuse, metabolic syndrome, and autoimmune disorders, the cellular and pathological mechanisms leading to hepatic fibrosis and - as an end-stage - cirrhosis are relatively common and uniform. Liver fibrosis is characterized by an accumulation of extracellular matrix proteins, and activated hepatic stellate cells (HSC), portal fibroblasts and myofibroblasts have been identified as major collagen-producing cells in the injured liver. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating an inflammatory phase resulting in the massive release of proinflammatory cytokines and chemokines as well as activation of HSC. Recent studies demonstrate that these actions are only partially conducted by liver-resident macrophages, but largely depend on recruitment of monocytes into the liver, namely of the inflammatory Gr1+ (Ly6C+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 participate in regulating monocyte subset infiltration. Macrophages, on the other hand, display a remarkable plasticity and can differentiate into functionally diverse subtypes, e.g. ‘classically activated’ M1 and ‘alternatively activated’ M2 macrophages. Experimental animal models indicate that monocytes/macrophages are not only critical for fibrosis progression, but also for fibrosis regression, because macrophages can also degrade extracellular matrix proteins and exert anti-inflammatory actions. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.