Translational research : the journal of laboratory and clinical medicine
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Review
Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction.
Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and β-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. ⋯ High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic β cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and β-cell dysfunction.
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Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway, although the drivers and site of the inflammation differ between diseases. Asthmatics with a neutrophilic airway inflammation are associated with a poor response to corticosteroids, whereas asthmatics with eosinophilic inflammation respond better to corticosteroids. Biologicals targeting the Th2-eosinophil nexus such as anti-interleukin (IL)-4, anti-IL-5, and anti-IL-13 are ineffective in asthma as a whole but are more effective if patients are selected using cellular (eg, eosinophils) or molecular (eg, periostin) biomarkers. ⋯ Currently, several other novel mediator-targeted drugs are undergoing clinical trials. As with asthma specifically targeted treatments may be of most benefit in specific COPD patient endotypes. The use of novel inflammatory mediator-targeted therapeutic agents in selected patients with asthma or COPD and the detection of markers of responsiveness or nonresponsiveness will allow a link between clinical phenotypes and pathophysiological mechanisms to be delineated reaching the goal of endotyping patients.
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There is no Food and Drug Administration-approved treatment for acute respiratory distress syndrome (ARDS), in spite of the relatively large number of patients with the diagnosis. In this report, we provide an overview of preclinical studies and a description of completed and future clinical trials in humans with ARDS. Preclinical studies dealing with acute lung injury have suggested roles for complement and complement receptors, as well as the evolving role of histones, but details of these pathways are inadequately understood. ⋯ Various cell growth factors are being considered for clinical study. Interventions to block complement activation or its products are under consideration. Stem cell therapies have shown efficacy in preclinical studies, which have motivated phase I/II trials in humans with ARDS.
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Our Introductory Commentary relates to many topics that are linked to inflammatory responses and how these responses are regulated in order to promote healing of damaged tissues and bring about effective clearance of infectious agents. In non-infectious situations, cells and tissues release products (danger associated molecular patterns) that can trigger damaging inflammatory responses. ⋯ With development of new technologies such as advanced genomic analysis, highly sensitive and sophisticated mass spectrometry and related approaches, as well as the ability to employ mutagenesis induction, we are beginning to define highly sophisticated molecular pathways that previously were opaque. This progress may well have clinical relevance, and we may be on the edge of a scientific revolution in the broad area of inflammation.
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Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. ⋯ Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.