The inflammatory response

Myocardial ischemia is associated with an inflammatory response that further contributes to myocardial injury and ultimately leads to myocardial healing and scar formation. Myocardial necrosis has been associated with complement activation and free radical generation that trigger cytokine cascades and upregulate chemokines expression. Mononuclear cell chemoattractants, such as the CC chemokines CCL2/Monocyte 

Interleukin-8 and C5a are released in the ischemic myocardium and may have a crucial role in neutrophil recruitment.29 Neutrophils are cells rich in oxidant species and proteolytic enzymes and can cause cell injury. In fact, annexin 1, a potent inhibitor of neutrophil extravasation in vivo was shown to protect the heart against ischemia and reperfusion injury.30 However, the importance of neutrophil in causing myocardial damage in the context of ischemia and reperfusion is now questioned. Experimental evidence shows that the time course of neutrophil accumulation in postischemic myocardium seems to be different from the time course of injury, myocardial injury is observed in neutrophil free conditions and anti-inflammatory interventions do not consistently limit infarct size, reviewed by Baxter.31 

Cytokines also exert direct negative inotropic effects via paracrine and autocrine modulation. This negative inotropic effect appears early (2-5min) and at later stages.32 Tumor necrosis factor (TNF-a), interleukin (IL-6) and (IL-1) are all shown to reduce myocardial contractility acting in synergistic and cascade-like reactions. 

IL-1 increases nitric oxide (NO) production by upregulating the synthesis of iNOS.35 This cytokine acts also via an NO-independent mechanism and causes downregulation of calcium regulating genes with subsequent depressed myocardial contractility.36 

IL-6 levels are elevated in patients with acute myocardial infarction. IL-6 is secreted by mononuclear cells in the ischemic area and is also produced by cardiac myocytes. IL-6 apart from its inflammatory effect regulates contractile function by its acute effect on calcium transients.37 

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The wide range of inflammation-related factors that adipocytes secrete is linked to the inflammatory response that the tissue exhibits in obesity [1]. Obesity in general, like an increasing number of other diseases, is characterised by a state of mild chronic inflammation, and adipose tissue plays a central role in this. The production of most inflammation-related adipokines increases markedly in obesity and there is an elevated circulating level of a number of these factors as well as of other inflammatory markers such as C-reactive protein (CRP). The increased production of inflammatory adipokines (and decreased production of adiponectin with its anti-inflammatory action) in the obese is considered to play a critical role in the development of the obesity-associated pathologies, particularly type 2 diabetes and the metabolic syndrome [1]. 

Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone, flunisolide) appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status they may also reduce the risk of myocar dial infar ction, but they do not modify the longterm decline in lung function. Whether- steroids affect mortality remains unclear. Many patients appear to be resistant to steroids and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid ther apy. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side-effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice. At the normal doses systemic side-effects of inhaled steroids have not been firmly established. The current recommendation is that the addition of inhaled gluco-coiticosteroids to bronchodilator treatment is appropriate for patients with severe to veiy sever e COPD. 

The objectives of the inflammatory response can be viewed as a hierarchical ordered panel of events. The most successful consequence of an inflammatory response is the complete restoration of function and structure of the affected tissue, also denoted as resolution. If this is not possible, inflammation aims for healing by repair and replacement of lost tissue by scar tissue. 

Chapman GA, Moores K, Harrison D, Campbell CA, Stewart BR, Strijbos PJ (2000) Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J Neurosci 20 RC87... 

Inflammation is a non-specific reaction which can be induced by a variety of agents apart fiom microorganisms. Lymphokines and derivatives of arachidonic acid, including prostaglandins, leukotrienes and thromboxanes are probable mediators of the inflammatory response. The release of vasoactive amines such as histamine and serotonin (5-hydroxytryptamine) firm activated or damaged cells also contribute to inflammation. 

ROM production by peripheral blood monocytes Production of ROM by peripheral blood monocytes in response to a variety of stimuli is increased in patients with active IBD (Table 10.2), su esting that such cells may respond to local stimulants within the gut more readily than in normal subjects or those with quiescent disease, and so may play a role in perpetuating the inflammatory response, cent studies have su ested that peripheral blood monocytes in Crohn s disease may be primed by the baaerial cell wall products LPS and peptidoglycanpolysaccharide (Muraki et al., 1992). 

Inflammatory cell phenomenon are also contributors to lipid peroxidation. Activated neutrophils may adhere to damaged endothelium and amplify traumatic, ischaemic or ischaemia-reperfiision injury. Many cyclooxygenase products of the metabolism of atachidonic acid modulate the inflammatory responses of cells. Macrophages, neutrophils and microglia are important sources of reactive oxygen at the injury site. When activated, they produce a respiratory burst that is traced to activated nicotinamide adenine dinucleotide (NADPH/NADH) oxidase. 

Th2 lymphocytes are one of the primary factors initiating and perpetuating the inflammatory response.7 In addition, proinflammatory mediators such as the leukotrienes generated during mast cell degranulation can increase vascular permeability, leading to airway edema and increased mucus production.8 Eosinophilic infiltration of the airways is a hallmark of asthma, and activated eosinophils can cause bronchoconstriction and AHR.9... 

Treatment of severe acute asthma includes the use of oxygen for the rapid reversal of hypoxemia, a short-acting P2-agonist to reverse airway constriction, and a systemic corticosteroid to attenuate the inflammatory response.1 Close monitoring of objective measures such as FEVi or PEF is important to quantify the response to therapy. Because recovery from exacerbations is often gradual, intensified therapy should be continued for several days. 

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