Inflammation is the principal defence mechanism against microbial infection and host injury. Neutralization and elimination of the offending insult ideally prompts resolution of inflammation and repair of damaged tissues. However, excessive or dysregulated inflammatory responses together with inadequate repair contribute to persisting tissue damage that underlies many inflammatory pathologies. An important recent advance is the discovery that resolution of inflammation involves tightly controlled self-limiting and active resolution programs. An emerging central paradigm is that effective resolution of inflammation depends on inhibition of neutrophil influx, promotion of monocyte recruitment, redirecting neutrophils to apoptosis, rapid clearance of infiltrating neutrophils and regeneration of disrupted tissue structures. During the past years, a number of novel cellular and molecular anti-inflammatory and pro-resolution mediators have been identified. Of these, protein mediators, such as annexin-1 and novel classes of lipid mediators, including lipoxins, resolvins, protectins and maresins, synthesized via the cyclooxygenase-2 and lipoxygenase interaction pathways of arachidonic acid and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) metabolism are potent inhibitors of pro-inflammatory cytokine production, and neutrophil chemotaxis and trafficking in vivo. Most of these mediators also promote recruitment of peripheral blood monocytes and facilitate clearance of apoptotic cells by promoting their phagocytosis by monocyte-derived macrophages in a nonphlogistic fashion. Beta-2 integrin-mediated outside-in signaling, cyclin-dependent kinases, proliferating cell nuclear antigen (PCNA) and myeloid nuclear differentiation antigen (MNDA) have been demonstrated to modulate neutrophil apoptosis, another potential control point in resolving inflammation. Delayed neutrophil apoptosis and/or impaired phagocytosis by macrophages prolong and aggravate tissue injury. Annexin-1, lipoxins and resolvins are proving to be highly effective therapeutics in a variety of experimental disease models, including acute lung injury, asthma, cardiovascular disease, renal ischemia-reperfusion, glomerulonephritis, arthritis, chronic liver disease, periodontitis, gastritis and polymicrobial sepsis. Moreover, resolvin E1 exerts promising beneficial actions in patients with dry eye syndrome. Induction of neutrophil apoptosis by R-roscovitine or overriding pro-survival signals by lipoxins enhances early inflammatory resolution in a number of murine models. Lipoxins enhance NO production, which together with other gaseous mediators could exert pro-resolving actions. Altering local adenosine signaling may restore tissue function and targeting the complement cascade or complement receptors may attenuate excessive inflammation in sepsis and autoimmune diseases. Adrenomedullin, which contributes to mucosal immunity, or the bactericidal peptide cathelicidin LL-37, which synergizes with LTB4 to enhance innate immune responses, offer additional opportunities for pharmacological intervention. While currently there are no drugs in the clinic that are purposefully based on elicitation of pro-resolving pathways, drugs that mimic the actions of endogenous pro-resolution factors or enhance their synthesis hold promise as disease-modifying interventions. Development of such drugs may fulfill urgent clinical needs to enhance resolution of inflammation.
Inflammation is the principal defence mechanism against microbial infection and host injury. Neutralization and elimination of the offending insult ideally prompts resolution of inflammation and repair of damaged tissues. However, excessive or dysregulated inflammatory responses together with inadequate repair contribute to persisting tissue damage that underlies many inflammatory pathologies. An important recent advance is the discovery that resolution of inflammation involves tightly controlled self-limiting and active resolution programs. An emerging central paradigm is that effective resolution of inflammation depends on inhibition of neutrophil influx, promotion of monocyte recruitment, redirecting neutrophils to apoptosis, rapid clearance of infiltrating neutrophils and regeneration of disrupted tissue structures. During the past years, a number of novel cellular and molecular anti-inflammatory and pro-resolution mediators have been identified. Of these, protein mediators, such as annexin-1 and novel classes of lipid mediators, including lipoxins, resolvins, protectins and maresins, synthesized via the cyclooxygenase-2 and lipoxygenase interaction pathways of arachidonic acid and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) metabolism are potent inhibitors of pro-inflammatory cytokine production, and neutrophil chemotaxis and trafficking in vivo. Most of these mediators also promote recruitment of peripheral blood monocytes and facilitate clearance of apoptotic cells by promoting their phagocytosis by monocyte-derived macrophages in a nonphlogistic fashion. Beta-2 integrin-mediated outside-in signaling, cyclin-dependent kinases, proliferating cell nuclear antigen (PCNA) and myeloid nuclear differentiation antigen (MNDA) have been demonstrated to modulate neutrophil apoptosis, another potential control point in resolving inflammation. Delayed neutrophil apoptosis and/or impaired phagocytosis by macrophages prolong and aggravate tissue injury. Annexin-1, lipoxins and resolvins are proving to be highly effective therapeutics in a variety of experimental disease models, including acute lung injury, asthma, cardiovascular disease, renal ischemia-reperfusion, glomerulonephritis, arthritis, chronic liver disease, periodontitis, gastritis and polymicrobial sepsis. Moreover, resolvin E1 exerts promising beneficial actions in patients with dry eye syndrome. Induction of neutrophil apoptosis by R-roscovitine or overriding pro-survival signals by lipoxins enhances early inflammatory resolution in a number of murine models. Lipoxins enhance NO production, which together with other gaseous mediators could exert pro-resolving actions. Altering local adenosine signaling may restore tissue function and targeting the complement cascade or complement receptors may attenuate excessive inflammation in sepsis and autoimmune diseases. Adrenomedullin, which contributes to mucosal immunity, or the bactericidal peptide cathelicidin LL-37, which synergizes with LTB4 to enhance innate immune responses, offer additional opportunities for pharmacological intervention. While currently there are no drugs in the clinic that are purposefully based on elicitation of pro-resolving pathways, drugs that mimic the actions of endogenous pro-resolution factors or enhance their synthesis hold promise as disease-modifying interventions. Development of such drugs may fulfill urgent clinical needs to enhance resolution of inflammation.