1,721,291 research outputs found
The rise and fall of platelet-activating factor as a mediator of asthma
No full textPlatelet-activating factor (PAF) has been proposed as a central inflammatory mediator in asthma. It is a potent bronchoconstrictor agent, and induces persistent bronchial heperresponsiveness in animal models. Eosinophils are chemoattracted by PAF, and are themselves major sources of PAF. The 'PAF hypothesis' proposes that PAF over-production, possibly by eosinophils, perpetuates the eosinophilia and bronchial hyperresponsiveness that are cardinal features of asthma. However, inhaled PAF does not appear to cause a specific eosinophil influx into the human lung and does not reproducibly cause bronchial hyperresponsiveness in man. Measurements of PAF in biological fluids are difficult to interpret and over-production of PAF has never been convincingly demonstrated in asthma. Potent and specific PAF antagonists have failed to block bronchoconstrictor responses and bronchial hyperrresponsiveness after inhaled allergen challenge. Trials of PAF antagonists in clinical asthma have failed to show any improvements in lung function, symptoms, bronchial responsiveness, use of rescue medication, or quality of life. The concept that PAF has a role in the pathophysiology of asthma is no longer realistically tenable, but the episode may provide instructive lessons for future research.</p
The role of eosinophils and neutrophils in inflammation
No full textThe eosinophil is well recognized as a central effector cell in the inflamed asthmatic airway. Eosinophils release toxic basic proteins and lipid mediators such as cysteinyl-leukotrienes that cause bronchial epithelial damage and airflow obstruction. Eosinophil-selective cytokines and chemokines including interleukin (IL)-5, eotaxin and RANTES may represent targets for novel asthma therapies. In contrast, the role of the neutrophil in asthma remains relatively obscure. Recent evidence from the ENFUMOSA project and elsewhere suggests that neutrophils not only contribute to acute asthma exacerbations, but also are present in high numbers in the airways of patients with chronic severe asthma. Production by neutrophils of lipid mediators, reactive oxygen intermediates (ROI) and proteases such as elastase, may contribute to airflow obstruction, epithelial damage and remodelling. Leukotriene B4 and cytokines such as IL-8, granulocyte- macrophage colony stimulating factor (GM-CSF), and tumour necrosis factor (TNF)α chemoattract neutrophils and reduce neutrophil apoptosis, and selective agents directed against these may prevent neutrophil influx and accumulation. Airway neutrophilia remains apparent in severe asthma patients even after treatment with high doses of corticosteroids. In vitro, corticosteroids paradoxically enhance neutrophil survival by reducing apoptosis, so corticosteroid therapy may exacerbate neutrophil activity in vivo. Both corticosteroids and cytokines may suppress neutrophil apoptosis by upregulating endogenous synthesis of leukotriene (LT)B4. Specific blockade of LTB4 synthesis or LTB4 receptors may induce neutrophil apoptosis and combat the unwanted effects of high-dose steroids on neutrophil survival. Phagocytosis of apoptotic neutrophils stimulates important signals that down- regulate pro-inflammatory cytokine production by macrophages, allowing resolution and repair processes to prevail.</p
Leukotriene generation
No full textLeukotriene modifier drugs do not cause bronchodilation in normal subjects, so the efficacy of therapy with leukotriene synthesis inhibitors (LTSI) and leukotriene receptor antagonists (LTRA) in asthmatic patients is a function of excessive leukotriene production and the responsiveness of asthmatic airways to these mediators. Clinical trials of LT modifier drugs in challenge models of asthma show that cys-LT synthesis represents a final common pathway for acute bronchoconstriction in response to allergic and nonallergic stimuli [1]. Increasingly, evidence suggests that in addition to these acute mast cell-dependent responses, chronic cys-LT production in asthma depends on infiltrating inflammatory cells including eosinophils, and even that cys-LT production by structural airway cells including bronchial epithelium, airway smooth muscle and vascular endothelium may contribute to airway remodelling. This review will focus on clinical, genetic and immunopathological studies that throw light on the mechanisms and cellular sources of excess cys-LT synthesis in the asthmatic lung
IL‐5 priming of eosinophil function in asthma
No full textEosinophils were once thought to help to resolve acute asthma by scavenging allergens and cellular debris in the airway, but their prevalence in the airways and blood of persistent asthmatics and their ability to produce toxic granule proteins, pro-inflammatory cytokines, oxygen radicals and lipid mediators incriminates them as principal culprits of airway inflammation in asthma
ASTHMA | Aspirin-Intolerant
No full textAspirin-intolerant asthma (AIA) is a phenotype experienced by 10-20% of persistent asthmatics, in whom acute bronchoconstriction is induced by ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs share the ability to inhibit synthesis of prostanoids by blockade of cyclooxygenase (COX). Acute reactions to NSAIDs can be life threatening and may be associated with rhinoconjunctival and dermal symptoms. Drugs that selectively inhibit COX-2 appear to be better tolerated than nonselective inhibitors of COX-1 and COX-2. Patients with AIA usually have persistent underlying asthma, often associated with nasal polyposis. Pathologically, the bronchial and nasal airways of AIA subjects show chronic eosinophilia, with evidence of activation of eosinophils and mast cells during acute reactions. The etiology of AIA is unclear, but the proposed mechanism focuses on the inhibition by NSAIDs of the synthesis of a prostanoid, putatively prostaglandin E 2, that would normally suppress local inflammatory reactions. The consequent synthesis of cysteinyl-leukotrienes and other leukocyte-derived mediators contributes to bronchoconstriction and other acute features. Treatment of AIA involves avoidance of NSAIDs combined with conventional management of underlying asthma, with 75% of AIA patients requiring corticosteroids. Controlled desensitization with regular doses of an NSAID can provide protection against acute reactions.</p
Anti-inflammatory mechanisms of leukotriene modulators
No full textModels to explain the cytokine and chemokine mechanisms of airway eosinophilia in asthma must now take into account the definitive evidence from clinical trials of specific leukotriene modulators that cysteinyl-LTs make a substantial, perhaps even the predominant, contribution to eosinophil migration in vivo. Indeed, until the advent of clinical trials of relevant cytokine antagonists, the leukotriene modulators may remain the only family of drugs with a known and specific mechanism of action that are capable of suppressing airway and blood eosinophilia. Recent evidence that at least part of the eosinophilic activity of cys-LTs may depend on secondary release of eosinophilopoietic cytokines such as IL-5 by T lymphocytes and other cells [9,38] should promote further study of the effects of cys-LTs on cytokine expression in leucocytes and airway cells.</p
Biosynthesis of cysteinyl-leucotrienes in aspirin-intolerant asthma
No full textMost medical concern over the worldwide use of aspirin (acetylsalicylic acid), the leading over-the-counter analgesic in many countries, has focused on the rare occurrences of Reye's syndrome (encephalopathy with hepatic failure) and gastric erosion in patients taking large aspirin doses for rheumatoid arthritis. Hypersensitivity to aspirin manifested as severe respiratory dysfunction has been relatively disregarded. Adverse respiratory reactions to aspirin and other non-steroidal anti-inflammatory drugs (NSAID) are well documented in the literature, but frequently overlooked in asthmatic patients. Only 3–5% of adult asthmatics have a clinical history of NSAID hypersensitivity, but this rises to about 20% when asthmatics are challenged with NSAIDs in the laboratory.Aspirin-intolerant asthma (AIA) is a syndrome with features reminiscent of a protracted viral respiratory infection. Classic symptoms of chronic rhinoconjunctivitis, nasal polyps and bronchial asthma typically define the syndrome [ 1]. The onset of AIA is insidious, with a peak incidence around 35 years of age, although AIA has been observed in adolescents. AIA usually persists for life, but in some cases the disease is self-limiting. In AIA patients, acute hypersensitivity reactions to NSAIDs are superimposed upon a background of chronic, severe asthma. Acute asthma attacks may be precipitated following ingestion of even small doses of aspirin (frequently less than 80 mg), often accompanied by congestion of the conjunctiva and nasal mucosa. AIA patients usually have adverse reactions to a wide range of NSAIDs. Bronchoconstriction may be severe and life-threatening, requiring hospital admission and sometimes mechanical ventilation. Up to 25% of hospital admissions for acute asthma requiring emergency mechanical ventilation may be caused by NSAID ingestion. Aspirin and other NSAIDs must be avoided by AIA patients, although the atypical NSAID paracetamol and the new cyclooxygenase-2-selective NSAIDs (e.g. meloxicam) may be better tolerated. Even in the absence of exposure to NSAIDs, the underlying severity of chronic asthma necessitates oral corticosteroid therapy in 50% of AIA patients. Desensitization, in which incremental oral doses of aspirin extinguish adverse reactions as long as the drug is regularly ingested, may alleviate clinical symptoms, especially rhinosinusitis. This review will discuss the evidence for a fundamental abnormality in cysteinyl-leukotriene synthesis in AIA patients, which provides a rationale for the clinical use of leucotriene modifier (LM) drugs in these patients
Eosinophils: provokers or bystanders in asthma?
No full textUntil the late 1970s, eosinophils were thought to have a beneficial role in the asthmatic airway by phagocytosing allergen debris and effete inflammatory cells. During the 1980s, evidence began to point to eosinophils as critical players in severe and persistent asthma, and studies in man and in animals since the 1990s have implicated Th-2-type cytokines as key inducers of airway eosinophilia and bronchial hyperresponsiveness (BHR).The impact of eosinophilic inflammation on asthma pathophysiology has been increasingly questioned, particularly by studies that appear to disrupt the putative links between airway eosinophilia, bronchial hyperresponsiveness and airway remodelling. Both the extent and the pathophysiological importance of airway remodelling in asthma continue to be disputed, but recent studies suggest that remodelling is due to pathways distinct from those that cause eosinophil-mediated bronchoconstriction and epithelial damage.In addition, there is increasing recognition that distinct patterns of leukocyte cellularity in the airway may underlie the diverse clinical phenotypes of asthma, with neutrophils and macrophages implicated as effector cells in subgroups of patients. This paper will assess the evidence for provoker and bystander roles of eosinophils in asthma, and focus particularly on eosinophils as the putative source of cysteinyl-leukotrienes (cys-LT) in a major subpopulation of asthmatics, who may represent the optimal target population for LTRA therapy
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