Effects of Catecholamines on the Inflammatory Response

Patients with severe sepsis are often treated with vasoactive agents in an attempt to restore cardiovascular function. Catecholamines, either administered as part of sepsis therapy or endogenously released as part of the early host response to injury, can influence the activation of inflammatory pathways during severe infection. This brief review discusses current knowledge of the interactions between exogenous and endogenous catecholamines on the one hand, and inflammatory responses activated during sepsis on the other hand.     

Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

Bacterial infection triggers host inflammation through the activation of immune cells, leading to the elimination of bacteria. However, the regulatory mechanisms of the host inflammatory response remain unknown. Here we report that a subset of potent tolerogenic dendritic cells (DCs), regulatory DCs (DC(regs)), control the systemic inflammatory response. Unlike normal DCs, which produced proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS), DC(regs) produced fewer proinflammatory cytokines and instead preferentially produced interleukin-10 (IL-10), and these events involved the expression of IkappaBNS and Bcl-3 as well as cyclic AMP (cAMP)-mediated activation of protein kinase A (PKA). In addition, DC(regs) not only suppressed LPS-induced production of proinflammatory cytokines in macrophages, but also reduced their serum levels in mice. Furthermore, DC(regs) protected mice against the lethality induced by experimental endotoxemia and bacterial peritonitis. The inhibitory effect of DC(regs) against inflammatory responses involved the production of IL-10. On the other hand, naturally existing tolerogenic DC subsets producing IL-10, CD11c(low)CD45RB(high) DCs, also suppressed LPS-induced host inflammatory responses. Thus, a subset of tolerogenic DCs act as potential regulators of the host inflammatory response, and they might have preventive and therapeutic potential for the treatment of systemic as well as local inflammatory diseases.     

细胞自噬与心血管疾病中炎症反应的相关性

细胞自噬既是保守的细胞防御机制,也是程序性细胞死亡(即调亡)机制,其可维持细胞自身内环境的稳态。心血管疾病多伴有炎症反应并与细胞自噬密切相关。新近研究表明:一方面,自噬可以通过清除堆积蛋白和保持线粒体稳态对抗心血管疾病的炎症反应,此效应可能与抑制炎症小体以及钙蛋白酶依赖的白介素-1α的活性有关;另一方面,自噬在某些情况下也可促进炎症反应,自噬相关蛋白和高尔基体重组-堆叠蛋白参与了自噬的促炎效应。以本文简要综述细胞自噬在心血管疾病炎症反应中的作用,探讨自噬与炎症反应的相关分子机制,为心血管疾病中炎症反应的治疗提供新的思路。     

Immunomodulation by antimicrobial drugs

Immunomodulation aims at either enforcement of host defence mechanisms or dampening of the inflammatory response of the host. Thus, immunomodulatory drugs may enhance host defence by either stimulating the inflammatory response or inhibiting the counter-regulatory, anti-inflammatory response. On the other hand, the response of the host may be down-modulated through inhibition of the inflammatory response or induction of counter-regulatory, anti-inflammatory mechanisms. Antimicrobial drugs may have such immunomodulatory effects, but so far these effects have not been exploited clinically.     

The role of defensins in the pathogenesis of chronic-inflammatory bowel disease

Defensins are endogenous antimicrobial peptides with a broad activity spectrum. Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed. As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier. This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the "normal" luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases. A defective defensin expression may well explain these phenomena. Indeed, Crohn's disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-defensins 2 and 3) response is reduced. Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response. Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn's disease is a defensin deficiency syndrome.     

New aspects of asthma.

It has now become apparent that asthma, even in its mildest clinical manifestation, is a chronic inflammatory condition of the airways. There have been important advances in understanding the special features of inflammation in asthmatic airways and the role of critical inflammatory cells such as mast cells (important in the acute inflammatory response) and eosinophils, macrophages and T-lymphocytes (involved in the chronic inflammatory response). Many inflammatory mediators have been implicated in asthma, and the development of mediator antagonists suggests that sulphidopeptide leukotrienes may play an important role in bronchoconstrictor responses. Cytokines released from many different cells in the airways are likely to be important in orchestrating and perpetuating the chronic inflammatory response. Chronic inflammation has effects on airway vessels, mucus secretion, smooth muscle and nerves, with evidence to suggest that there are structural changes which may lead to persistent airway abnormalities. The therapeutic implication of these new discoveries is that much earlier use of anti-inflammatory treatments (such as inhaled steroids) is preferable to reliance on bronchodilators which do not control the underlying inflammatory process.     

The experimental basis of intestinal suturing

Factors that incite inflammation at the healing wound prolong the lag period of wound healing and delay the return of strength at the suture line. Inflammation activates bowel-wall collagenase, which degrades the collagen within the wound, eroding the foundation in which sutures are anchored. Experimental studies have compared the impact of various surgical techniques. Sutures placed by hand uniformly invoke an inflammatory response because dragging the thread through the bowel wall injures tissue. Single-layer anastomoses heal more rapidly than double-layer suture lines. The inner layer causes avascular necrosis of the inverted cuff. Experimental studies have not clearly shown the superiority of inverting suture lines over everting ones. Experimental studies done over the last century indicate that the single-layer inverting anastomosis recommended by Lembert and Halstead adequately compensates for enteric wound weakness during the lag period. Other techniques of sewing an anastomosis provide no clear advantage. Other factors that incite inflammation also delay enteric wound healing. Debris, necrotic tissue, or infection illicit an inflammatory response with detrimental effects on the anastomosis. Antibiotics, by assisting in the control of infection or by minimizing the size of an inoculum help speed healing. Stapling devices violate many of the doctrines of intestinal suturing. Experimental studies suggest, however, that staple lines incite a minimal inflammatory response. Consequently, wounds closed with stapling devices regain strength more rapidly than those closed with traditional surgical techniques.     

Zinc supplementation in the elderly reduces spontaneous inflammatory cytokine release and restores T cell functions

Aging is associated with low-grade inflammation on the one hand and mild zinc deficiency on the other. These conditions contribute to decreased immune functions, resulting in increased incidences of infections and autoimmune diseases. The aim of this study was to give more insight into the question, to what extent is low-grade inflammation caused by zinc deficient status. Here we report the effect of improved intracellular zinc status on low-grade inflammatory activity in 19 healthy elderly subjects. Our experiments show that adjustment of labile zinc by moderate zinc supplementation reduces spontaneous cytokine release and defects in termination of inflammatory activity. This results in reduced amounts of unspecific preactivated T cells and leads to improved T cell response upon mitogenic stimulation. Therefore, in contrast to other anti-inflammatory drugs, zinc does not suppress, but improves immune reaction upon pathogen invasion. These results suggest that mildly zinc-deficient, healthy elderly subjects might benefit from moderate zinc supplementation due to a more balanced immune response with reduced incidences of infections and autoimmune diseases.     

Adenovirus-mediated gene transfer in the ovine pituitary gland is associated with hypophysitis

Gene therapy for pituitary disease requires evaluation for safety as well as efficacy. We have reported results of adenovirus-mediated gene transfer using the sheep as a large animal model that allows longitudinal evaluation of hormone secretion and have confirmed high levels of transgene expression up to 7 days after direct stereotaxic injection into the pituitary gland. Here we report the results of detailed histological examination of the pituitary glands from animals injected with two recombinant adenoviruses expressing the beta-galactosidase marker gene, or with saline vehicle to control for the potential tissue-disruptive effect of the injection volume itself. Pituitaries injected with saline showed no evidence of inflammatory response apart from occasional minor foci of apoptosis. In all other respects they were indistinguishable from normal uninjected control pituitary glands. Glands injected with recombinant adenoviruses containing either the hCMV-beta-gal or the hPRL-beta-gal transgene, on the other hand, displayed variable degrees of inflammatory response, with periglandular fibrosis, lymphocytic infiltrate and venulitis in almost all cases. Focal necrosis and/or apoptosis was noted in six of nine cases. In summary, we have found evidence of severe inflammatory reaction within the first seven days of adenovirus injection, amounting to significant hypophysitis. The histological extent of this reaction has not previously been recognised by studies of the efficacy of gene transfer in rodents, and was underestimated by immunocytochemical studies of hormone and transgene expression. The findings emphasise the need for careful evaluation of the safety of endocrine gene therapy, and for caution with the dose of vector used.     

炎症反应在易损斑块中的作用及其机制研究进展

炎症反应在易损斑块的形成和进展中发挥重要作用,同时调控血管局部病变及全身炎症状态。一些促炎性细胞和炎症因子使斑块纤维帽的抗张强度降低,坏死脂质内核增大,血管机械稳定性丧失和斑块破裂;另一方面,炎症反应的激活和代谢紊乱也会引起内皮功能不全、斑块侵蚀进而导致血栓形成。该过程主要由巨噬细胞和淋巴细胞等多种炎症细胞参与,并受到多种因素调控,包括胆固醇结晶和脂质递质、血管剪切力、血管新生及斑块内出血等。此外,机体还存在一些抑炎性分子,能避免易损斑块向破裂或侵蚀进展。促炎和抗炎反应的平衡影响急性冠状动脉事件的发生。因此,以炎症反应为靶点,筛选出有易损斑块的患者并干预,或可减少急性冠状动脉事件的发生和改善预后,具有重要临床价值。     

Pathophysiology of cardiac inflammation: molecular mechanisms

BACKGROUND: Inflammatory processes induced by rival infection are believed to be one of the major pathogenetic mechanisms in inflammatory dilated cardiomyopathy. Although the reason for progression to myocardial failure is not fully understood, postulated mechanisms include persistent viral infection alone or in combination with autoimmune processes. PATHOPHYSIOLOGY: Murine models of myocarditis have provided insight into the mechanisms by which autoimmune responses to cardiac antigens, probably in response to viral infection of the myocardium, arise and cause tissue pathology. Organ-specificity, cross-reactivity between microbial agents and cardiac tissue, and induction of tolerance to self-antigen are issues still at stake. In addition, cytokines mediate activation and effector phase of innate and specific immunity, which are both important in controlling viral infection. The innate immune response not only has an important protective function but also serves to initiate and regulate subsequent specific immune responses. In man, on the one hand specific T cells and antibodies against different cardiac tissue components have been demonstrated in myocardium and sera of patients with inflammatory cardiomyopathy, and on the other hand viral genome has been identified in endomyocardial biopsies due to the rapid development of new molecular biological techniques such as polymerase chain reaction (PCR), southern blot analysis and in-situ hybridization. But it is still a mater of debate whether virus infection itself, the ensuing immune response, or both, contribute to the deterioration of left ventricular function. CONCLUSION: Taking these mechanisms into account, screening for viral genome by PCR and detection of inflammatory infiltrates by immunohistochemistry are considered crucial for the establishment of a definite diagnosis thereby allowing for the initiation of specific therapeutic strategies.     

Modulation of systemic inflammatory response after cardiac surgery

Cardiac surgery and cardiopulmonary bypass initiate a systemic inflammatory response largely determined by blood contact with foreign surfaces and the activation of complement. It is generally accepted that cardiopulmonary bypass initiates a whole-body inflammatory reaction. The magnitude of this inflammatory reaction varies, but the persistence of any degree of inflammation may be considered potentially harmful to the cardiac patient. The development of strategies to control the inflammatory response following cardiac surgery is currently the focus of considerable research efforts. Diverse techniques including maintenance of hemodynamic stability, minimization of exposure to cardiopulmonary bypass circuitry, and pharmacologic and immunomodulatory agents have been examined in clinical studies. This article briefly reviews the current concepts of the systemic inflammatory response following cardiac surgery, and the various therapeutic strategies being used to modulate this response.     

Role of Fas/Fas ligand interaction in ischemia-induced collateral vessel growth.

Fas ligand (FasL) is a death factor that induces apoptosis in cells bearing its receptor, Fas. Accumulating evidence indicates that the Fas/FasL system is involved not only in apoptosis but also in cell-activation signals. Recently, it was reported that local stimulation of Fas in vivo using an agonistic antibody triggers inflammatory cell infiltration and neoangiogenesis independently of apoptosis. On the other hand, Fas/FasL interaction has been proposed to control the growth and development of new subretinal vessels. Here, we evaluated the potential involvement of Fas/FasL interaction in collateral development in response to tissue ischemia. Hindlimb ischemia was induced in C57BL/6J (wild-type), B6-gld(FasL -/-), and B6-lpr(Fas -/-) mice by resection of the right femoral artery. The blood flow recovery of FasL -/- or Fas -/- mice was similar to that of wild-type mice, as determined using a laser Doppler imaging system. There was no significant difference in capillary density of the ischemic calf muscle among the mice, as determined by anti-CD31 immunostaining. We did not find any difference in the number of infiltrating inflammatory cells or in vascular endothelial growth factor expression. These results indicate that postnatal angiogenesis in response to acute ischemia can occur independently of the endogenous Fas/FasL interaction.     

Alpha-thrombin stimulates expression of macrophage migration inhibitory factor in skin fibroblasts

Macrophage migration inhibitory factor (MIF) is induced by various stimuli such as wounds and infection and regulates inflammatory and immunological responses. To date, we have found increased expression of MIF during the wound healing process in rat skin. Immunohistochemical analysis demonstrated enhanced expression of MIF in wound skin lesions. On the other hand, alpha-thrombin, a multifunctional serine protease, plays an important role in wound healing with regard to induction of inflammatory cytokines such as interleukin-6 (IL-6). Accordingly, we examined the effect of alpha-thrombin on MIF production in human skin fibroblasts. Alpha-thrombin significantly stimulated MIF secretion into culture medium of fibroblasts quantitated by an enzyme-linked immunosorbent assay (ELISA). Consistent with this, we observed the upregulation of MIF mRNA in response to alpha-thrombin by Northern blot analysis. Taken together, these results suggest that MIF produced by fibroblasts in response to alpha-thrombin plays an important regulatory role in wound repair.     

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.     

The inflammatory response in pneumonia

Summary In normal conditions, alveolar macorphage (AM) is the main cell that respond against to bacteria that reach lower airways. However, if the microbial inoculum is too high or too virulent to be stopped by AM alone, these cells recruit polymorphonuclear neutrophils (PMN) into the alveoli from the vascular compartment. Cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8), secreted by the AM are able to attract PMN enhanced for phagocytosis are ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death. Other cytokines like interleukin-10 (IL-10) balance this response attenuating several inflammatory mechanisms. The inflammatory lung response in pneumonia has been well studied in animals and more recently in humans using bronchoalveolar lavage to measure some inflammatory mediators (TNF-α, IL-1β, IL-6, IL-8). From these studies, it seems that first, the inflammatory response to pneumonia is compartmentalized for most cytokines (in contrast to ARDS), except for IL-6 which is a general marker of inflammation. On the other hand, C-Reactive-Protein is an acute-phase protein synthesized by the liver through the stimuli of IL-6 that may be also an easy to measure marker of inflammation directly related to IL-6; second, some of these cytokines may be useful as prognostic markers; third, there is no clear relationship between the local lung bacterial burden and the intensity of the inflammatory response; fourth, the administration of G-CSF is a promising therapeutic approach still under clinical investigation. In the future the therapeutic goal in severe pneumonia will probably be to find the exact point at which inflammation is beneficial but not deleterious. The measurement of the inflammatory response could serve for this purpose. Received: 20 August 1997 Accepted: 2 December 1997     

Inflammation and ageing

An enhanced inflammatory state - i.e. "inflammatory/pathogen burden" - in the elderly on the one hand results from physiological immunosenescence and on the other hand is modified by the individual immune history: the latter is determined by sequential infectious/pathogenic events ("multiple hits"). Immunosenescence may prompt ageing of other organs. Cardiac ageing can be assessed by analysing heart rate variability. We present our hypothesis that the increasing "inflammatory/pathogen burden" of each organism during a lifetime significantly contributes to the cardiac ageing process. This hypothesis is grounded on the fact that a characteristic feature of the ageing heart - a narrowed heart rate variability - can be experimentally induced in humans by an inflammatory stimulus (endotoxin).     

Nitric Oxide Synthase Inhibition

Nitric oxide (NO) is synthesized from L-arginine in the human respiratory tract by enzymes of the NO synthase (NOS) family. Levels of NO in exhaled air are increased in asthma, and measurement of exhaled NO has been advocated as a noninvasive tool to monitor the underlying inflammatory process. However, the relation of NO to disease pathophysiology is uncertain, and in particular the fundamental question of whether it should be viewed primarily as beneficial or harmful remains unanswered. Exogenously administered NO has both bronchodilator and bronchoprotective properties. Although it is unlikely that NO is an important regulator of basal airway tone, there is good evidence that endogenous NO release exerts a protective effect against various bronchoconstrictor stimuli. This response is thought to involve one or both of the constitutive NOS isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS). Therefore, inhibition of these enzymes is unlikely to be therapeutically useful in asthma and indeed may worsen disease control. On the other hand, the high concentrations of NO in asthma, which are believed to reflect upregulation of inducible NOS (iNOS) by proinflammatory cytokines, may produce various deleterious effects. These include increased vascular permeability, damage to the airway epithelium, and promotion of inflammatory cell infiltration. However, the possible effects of iNOS inhibition on allergic inflammation in asthma have not yet been described and studies in animal models have yielded inconsistent findings. Thus, the evidence to suggest that inhibition of iNOS would be a useful therapeutic strategy in asthma is limited at present. More definitive information will require studies combining agents that potently and specifically target individual NOS isoforms with direct measurement of inflammatory markers.