BioAcyl Corp

The Inflammatory Response. The acute inflammatory response is a complex but highly coordinated sequence of events. (A) Onset begins with the production of soluble mediators, including chemokines and cytokines, by resident cells such as tissue-resident macrophages and dendritic cells at the site of infection/injury. Upregulation of cell adhesion molecules on circulating leukocytes and endothelial cells promotes the influx of granulocytes from the blood, which phagocytose and eliminate tissue debris and microorganisms through distinct intracellular mechanisms involving superoxide radicals, myeloperoxidase, proteases, and lactoferrins, and extracellular mechanisms such as neutrophil extracellular traps. Onset makes way for the next phase of the inflammatory response, resolution, once the inciting stimulus has been cleared. (B) Once eliminated, resolution processes result in the termination of proinflammatory mediator synthesis and catabolise/sequester remaining mediators present in the tissue. This prevents further leukocyte recruitment and infiltration, leading to apoptosis of leukocytes and subsequent efferocytosis by tissue-resident macrophages. (C) A new model in which resolution is not the end of the immune responses to infection/injury adds a third phase after onset and resolution termed post-resolution. This new phase is characterised by accumulation of immune cells in the tissue that persist even after successful resolution that bestows upon the tissue a state of ‘adapted homeostasis’ that alters the immune physiology of post-inflamed tissues. Importantly, we believe that the development of adapted homeostasis is context dependent in which overexuberant inflammation or defective resolution may lead to ‘maladapted homeostasis’ and creation of an environment conducive to the development of chronic disease. Clinician’s Corner The cause of many chronic inflammatory and autoimmune diseases remains elusive with most therapies aimed at halting inflammation in its tracks. In recent years, an appreciation of targeting resolution processes is being recognised as an alternative to current treatments such as NSAIDs, which are known to have immunosuppressive side effects. Defective resolution is implicated in a myriad of chronic diseases including: RA, SLE, COPD, atherosclerosis, and glomerulonephritis. Our understanding of resolution is evolving, and we now appreciate that there is a great deal of immunological activity occurring at a subclinical level after resolution in tissues that dictates immune responses to future inflammatory stimuli.