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Anti-inflammatory interventions—what has worked, not worked, and what may work in the future

Published:August 13, 2015DOI:https://doi.org/10.1016/j.trsl.2015.08.003
      The inflammatory response is central to effectively dealing with invasive infectious agents (bacteria, viruses, and protozoa) as well as in the setting of tissue and organ “sterile” injury (eg, ischemia-reperfusion injury, hemorrhagic shock, nonpenetrating trauma, and so forth) and in repair of damaged tissues. With infectious agents, activation of the acute inflammatory response occurs via the innate immune system, featuring local buildup of neutrophils (polymorphonuclear leukocytes [PMNs]) from the bone marrow and blood, as well as accumulation of blood mononuclear cells, which migrate into extravascular sites and mature into tissue macrophages. The emergence of new technologies for more than the past many decades has propelled research into the inflammatory response along many new directions. These new technologies include mass spectroscopy and related technologies, cloning and expression of peptides, new methods to rapidly purify peptides, proteins and lipids, and breakthrough technologies for sequencing of proteins, DNA, and RNA as well as their “editing.” The appearance of molecular biology along with the ability to clone and express purified peptides has allowed access to products that are homogenous and not contaminated with substances that could cause experimental artifacts. In the current issue, there is a wide range of mechanisms that can be linked to inflammatory injury. The heme oxygenase pathway generates carbon monoxide, which together with nitric oxide has been used in humans to suppress lung inflammatory responses.
      • Ryter S.W.
      • Choi A.M.K.
      Targeting heme oxygenase-1/carbon monoxide for therapeutic modulation of inflammation.
      Products of tryptophan metabolism may amplify inflammatory responses.
      • Santhanam S.
      • Alvarado D.M.
      • Ciorba M.A.
      Therapeutic targeting of inflammation and tryptophan metabolism in colorectal and gastrointestinal cancer.
      Various anti-inflammatory strategies have been used to treat chronic obstructive pulmonary disease and asthmatic conditions.
      • Durham A.L.
      • Caramori G.
      • Chung K.F.
      • Adcock I.M.
      Targeted anti-inflammatory therapeutics in lung disease.
      Several years ago, it was discovered that C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4) play key roles in entry of human immunodeficiency virus (HIV) into CD4+ T cells.
      • Kuritzkes D.R.
      HIV-1 entry inhibitors: an overview.
      • Henrich T.J.
      • Kuritzkes D.R.
      HIV-1 entry inhibitors: recent development and clinical use.
      Part of this discovery process was related to mutations occurring in CCR5 of humans, which impaired entry of HIV into T cells. Numerous synthetic inhibitors of CCR5 have been developed, which impair HIV entry into T cells, and some have been approved by the Food and Drug Administration (FDA) for clinical application. On the basis of this type of strategy, chemokine receptor antagonists may find application in the area of inflammatory diseases, such as inflammatory bowel disease, for which there is a dearth of clinically effective anti-inflammatory drugs. The “metabolic syndrome” can be manipulated by targeting the inflammatory system, including the NLR family, pyrin domain containing 3 (NLRP3) inflammasome.
      • Welty F.K.
      • Alfaddagh A.
      • Elajami T.K.
      Targeting inflammation in metabolic syndrome.
      Even in sickle cell disease, inflammatory targets have been suggested.
      • Owusu-Ansah A.
      • Ihunnah C.A.
      • Walker A.L.
      • Ofori-Acquah S.F.
      Inflammatory targets of therapy in sickle cell disease.
      Anti-inflammatory interventions after immune reconstitution in humans after bone marrow transplantation may provide clinically desirable outcomes.
      • Shahani L.
      • Hamill R.J.
      Therapeutics targeting inflammation in the immune reconstitution inflammatory syndrome.
      It is also clear that in acute lung injury both in mice and in humans, new targets (histones) have been suggested.
      • Standiford T.J.
      • Ward P.A.
      Therapeutic targeting of acute lung injury and ARDS.
      Similar strategies may be used in type I diabetes,
      • Cabrera S.M.
      • Henschel A.M.
      • Hessner M.J.
      Innate inflammation in type I diabetes.
      chronic renal disease,
      • Machowska A.
      • Carrero J.J.
      • Lindholm B.
      • Stenvinkel P.
      Therapeutics targeting persistent inflammation in chronic kidney disease.
      graft-vs-host disease,
      • Holtan S.G.
      • Arora M.
      Angiogenic factors and inflammation in steroid-refractory acute graft-versus-host disease.
      and in acute ischemic injury involving the heart.
      • Saxena A.
      • Russo I.
      • Frangogiannis N.G.
      Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges.
      Another poorly understood condition is nonalcoholic fatty liver disease, which may be emerging to be the most prevalent liver disease, with increased risk of liver-related and cardiovascular-related mortality.
      • Federico A.
      • Dallio M.
      • Godos J.
      • Loguercio C.
      • Salomone F.
      Targeting gut-liver axis for the treatment of non-alcoholic fatty liver disease: translational and clinical evidence.
      As this disease progresses, inflammation and fibrotic changes in liver appear and engagement of toll-like receptors may be linked to cytokine production by hepatocytes. Obviously, much more information is needed before a rational therapeutic approach can be considered. There are many new review articles describing numerous inhibitors and neutralizing monoclonal antibodies (mAbs) that block complement activation products, cytokines, or chemokines, to treat various inflammatory conditions.
      • Glassman P.M.
      • Balthasar J.P.
      Mechanistic considerations for the use of monoclonal antibodies for cancer therapy.
      • Prete M.
      • Perosa F.
      • Favoino E.
      • Dammacco F.
      Biological therapy with monoclonal antibodies: a novel treatment approach to autoimmune disease.
      • Risitano A.M.
      Current and future pharmacologic complement inhibitors.
      • Dinarello C.A.
      • Simon A.
      • van der Meer J.W.
      Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.
      The relationship between obesity, insulin-resistance, and pancreatic β cell dysfunction suggests a linkage between cytokine release from adipocytes and residential macrophages and signaling pathways activated by the cytokines, which all result in eventual apoptosis of pancreatic β cells and onset of type 2 diabetes.
      • Khodabandeloo H.
      • Gorgani-Firuzjaee S.
      • Panahi S.
      • Meshkani R.
      Molecular and cellular mechanisms linking inflammation to insulin resistance and beta cell dysfunction.
      Assuming these pathways cause the diabetic condition, it may be possible to intervene early on with targeted anti-inflammatory interventions.
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