LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression

Bacterial LPS triggers dramatic changes in gene expression in macrophages. We show here that LPS regulated several members of the histone deacetylase (HDAC) family at the mRNA level in murine bone marrow-derived macrophages (BMM). LPS transiently repressed, then induced a number of HDACs (Hdac-4, 5, 7) in BMM, whereas Hdac-1 mRNA was induced more rapidly. Treatment of BMM with trichostatin A (TSA), an inhibitor of HDACs, enhanced LPS-induced expression of the Cox-2, Cxcl2, and Ifit2 genes. In the case of Cox-2, this effect was also apparent at the promoter level. Overexpression of Hdac-8 in RAW264 murine macrophages blocked the ability of LPS to induce Cox-2 mRNA. Another class of LPS-inducible genes, which included Ccl2, Ccl7, and Edn1, was suppressed by TSA, an effect most likely mediated by PU.1 degradation. Hence, HDACs act as potent and selective negative regulators of proinflammatory gene expression and act to prevent excessive inflammatory responses in macrophages.

Recent developments in C5/C5a inhibitors

Complement factor 5a (C5a) is formed upon complement system activation in response to infection, injury or disease. Whilst C5a is a potent mediator of immune and inflammatory processes, excessive production or inadequate regulation of C5a has been implicated in the pathogenesis of numerous immuno-inflammatory diseases, predominantly through experimental studies utilising animal models of disease. Both acute and chronic conditions may benefit from C5a inhibition, including rheumatoid arthritis, inflammatory bowel disease, asthma, psoriasis, haemorrhagic shock and neurodegenerative conditions. The potentially broad clinical application for treatments that inhibit the activity of C5a at C5a receptors and the large global market for anti-inflammatory therapeutics have made C5a and the C5a receptor attractive targets for academic and commercial drug development programmes. in the past 5 years, interest in C5a as a drug target has grown substantially, and this activity has resulted in a collection of patents and scientific papers reporting novel C5a and C5a receptor inhibitors and antagonists, and generated a secondary stream of patent applications broadly claiming the use of C5/C5a inhibitors as a method of treating various immune and inflammatory conditions. This paper will review the physiology and pathophysiology of C5a and discuss the development of C5a and C5a receptor inhibitors in light of the recent scientific and patent literature.

The mononuclear phagocyte system

The mononuclear phagocyte system (MPS) has been defined as a family of cells comprising bone marrow progenitors, blood monocytes and tissue macrophages. Macrophages are a major cell population in most of the tissues in the body, and their numbers increase further in inflammation, wounding and malignancy. Their trophic roles for other cell types in development and homeostasis are becoming increasingly evident. The receptor for macrophage colony-stimulating factor (CSF-1R) is expressed in a large proportion of cells considered to be mononuclear phagocytes, including antigen-presenting dendritic cells, which can be considered a specialized adaptive state rather than a separate lineage. The unity of the MPS is challenged by evidence that there is a separate embryonic phagocyte lineage, by the transdifferentiation and fusion of MPS cells with other cell types, and by evidence of local renewal of tissue macrophage populations as opposed to monocyte recruitment. The concept of the MPS may have partly outlived its usefulness.

TRALI in 2 cases of leukemia

We describe transfusion-related acute lung injury (TRALI) in 2 acute leukemia cases to increase awareness of this under reported serious transfusion complication syndrome in multitransfused patients. There are a number of reports in multitransfused patients with nonmalignant disorders. However, reports of pediatric oncology patients are few, suggesting a lack of recognition or misdiagnosis of the syndrome. A disproportionately high number of fatalities in children is recorded in the literature. This highlights the need for increased awareness and appropriate treatment of this serious complication of transfusion. Although TRALI is initially a clinical diagnosis, the laboratory investigation is vital as it contributes to defining the pathogenesis of the syndrome and importantly facilitates the effective management of implicated donations and donors. An investigational strategy for suspected cases is presented and the results are discussed in the context of current proposed mechanisms for TRALI. As each transfused blood product is associated with a potential risk of TRALI, more frequent reports in patients receiving large volume or recurrent transfusion would be expected.

Beta-lactam allergy in adults with cystic fibrosis

Background: Allergic reactions to one or more beta-lactam antibiotic can pose a management problem in patients with cystic fibrosis (CF), and may limit antibiotic choice. Method: The aim of this study was to assess the prevalence of allergy to anti-pseudomonal beta-lactam antibiotics in an adult CF centre and to assess variables, which may contribute to the development of allergic reactions. A questionnaire-based interview and a review of medical records were performed. Results: Of the 150 patients, 54 (36%) had allergic reactions to one or more beta-lactam antibiotics and 20 (19%) had allergic reactions to multiple beta-lactam antibiotics. The proportion of patients allergic to specific beta-lactam antibiotics varied from 10% to 26%. Rates of reactions were highest for penicillins and cephalosporins, intermediate for carbepenems and lowest for aztreonam. Of all reactions, 40% occurred within 24 h of the commencement of an individual antibiotic course. Patients with one or more beta-lactam allergic reactions had received greater cumulative exposure (p < 0.0001), were older (p=0.016) and had lower lung function (p=0.037) than patients without a history of beta-lactam allergy. Cystic Fibrosis transmembrane regulator (CFTR) status, gender, peripheral blood eosinophil count and total IgE concentrations were not different in patients with allergic reactions. Conclusions: This study demonstrates that the prevalence of allergic reactions to beta-lactam antibiotics is high in adults with CF. Increasing age; cumulative exposure and decreasing FEV1 were associated with the development of allergy. (C) 2006 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

The influence of antioxidant supplementation on markers of inflammation and the relationship to oxidative stress after exercise

Interest in the relationship between inflammation and oxidative stress has increased dramatically in recent years, not only within the clinical setting but also in the fields of exercise biochemistry and immunology. Inflammation and oxidative stress share a common role in the etiology of a variety Of Chronic diseases. During exercise, inflammation and oxidative stress are linked via muscle metabolism and muscle damage. Because oxidative stress and inflammation have traditionally been associated with fatigue and impaired recovery from exercise, research has focused on nutritional strategies aimed at reducing these effects. In this review, we have evaluated the findings of studies involving antioxidant supplementation on alterations in markers of inflammation (e.g., cytokines, C-reactive protein and cortisol). This review focuses predominantly on the role of reactive oxygen and nitrogen species generated from muscle metabolism and muscle damage during exercise and on the modulatory effects of antioxidant supplements. Furthermore, we have analyzed the influence of factors such as the dose, timing, supplementation period and bioavailability of antioxidant nutrients. (C) 2007 Elsevier Inc. All rights reserved.