Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune–mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.
Macrophages are either classically (M1) or alternatively-activated (M2). Whereas this nomenclature was generated from monocyte-derived macrophages treated in vitro with defined cytokine stimuli, the phenotype of in vivo-derived macrophages is less understood. We com-
Eosinophil granulocytes reside in respiratory mucosa including lungs, in the gastro-intestinal tract, and in lymphocyte associated organs, the thymus, lymph nodes and the spleen. In parasitic infections, atopic diseases such as atopic dermatitis and asthma, the numbers of the circulating eosinophils are frequently elevated. In conditions such as Hypereosinophilic Syndrome (HES) circulating eosinophil levels are even further raised. Although, eosinophils were identified more than hundred years ago, their roles in homeostasis and in disease still remain unclear. The most prominent feature of the eosinophils are their large secondary granules, each containing four basic proteins, the best known being the eosinophil cationic protein (ECP). This protein has been developed as a marker for eosinophilic disease and quantified in biological fluids including serum, bronchoalveolar lavage and nasal secretions. Elevated ECP levels are found in T helper lymphocyte type 2 (atopic) diseases such as allergic asthma and allergic rhinitis but also occasionally in other diseases such as bacterial sinusitis. ECP is a ribonuclease which has been attributed with cytotoxic, neurotoxic, fibrosis promoting and immune-regulatory functions. ECP regulates mucosal and immune cells and may directly act against helminth, bacterial and viral infections. The levels of ECP measured in disease in combination with the catalogue of known functions of the protein and its polymorphisms presented here will build a foundation for further speculations of the role of ECP, and ultimately the role of the eosinophil.
Diffuse alveolar hemorrhage is a severe respiratory complication of systemic lupus erythematosus. The illness develops over hours to a few days and is the systemic lupus erythematosus-associated syndrome with highest mortality. Although no specific symptoms have been identified, a number of features are associated with diffuse alveolar hemorrhage, with a drop in blood hemoglobin the most prominent. Dyspnea, blood-stained sputum, diffuse infiltrates identified by chest imaging, elevated single breath-diffusing capacity for monoxide, thrombocytopenia and C3 hypocomplementemia are other commonly reported signs of diffuse alveolar hemorrhage. The etiology is not completely understood but many patients develop diffuse alveolar hemorrhage concomitant with lupus nephritis, suggesting immune complex-driven pathology. Biopsy studies have identified both cases with capillaritis and a bland non-inflammatory phenotype. An animal model of diffuse alveolar hemorrhage has indicated requirement of B lymphocytes and complement receptor-mediated apoptotic body phagocytosis by monocytes as part of the pathogenesis. This review will discuss considerations when diagnosing the condition and available therapies. Infections and other causes of hemorrhage have to be excluded as these require different treatment strategies. Methylprednisolone and cyclophosphamide remain the most commonly used therapies. Plasmapheresis and rituximab are other beneficial treatment options. A few studies have also considered intrapulmonary Factor VII therapy, extracorporeal membrane oxygenation and mesenchymal stem cell therapy. There is an unmet need of better definition of diffuse alveolar hemorrhages etiology and pathology for development of improved treatment strategies.
As our understanding of inflammatory resolution increases, drugs that trigger proresolution pathways may become significant in treating chronic inflammatory diseases. However, anti-inflammatory drugs are traditionally tested during the first hours of onset (i.e., to dampen leukocyte and edema formation), and their ability to trigger proresolution processes has never been investigated. Moreover, there is no model available to screen for putative proresolving agents. In this study, we present a new strategy to identify therapeutics for their ability to switch inflammation off and restore homeostasis. Injecting 1.0 mg of zymosan i.p. causes transient inflammation characterized by polymorphonuclear neutrophil clearance and dominated by recently described resolution-phase macrophages along with an innate-type lymphocyte repopulation, the latter being a marker of tissue homeostasis. In contrast, 10 mg of zymosan elicits an aggressive response characterized by classically activated macrophages leading to systemic inflammation and impaired lymphocyte repopulation. Although this latter model eventually resolves, it nonetheless represents inflammation in the clinically relevant setting of polymorphonuclear neutrophil/classically activated macrophage dominance driving a cytokine storm. Treating such a reaction therapeutically with proresolution drugs provides quantifiable indices of resolution—polymorphonuclear neutrophil/macrophage clearance, macrophage phenotype switching (classically activated to resolution phase), and repopulation with resolution-phase lymphocytes—cardinal signs of inflammatory resolution and homeostasis in the peritoneum. As an illustration, mice bearing peritonitis induced by 10 mg of zymosan- were given ibuprofen, resolvin E1, a prostaglandin D2 receptor 1 agonist, dexamethasone, rolipram, or azithromycin, and their ability to trigger resolution and homeostasis in this new inflammatory setting was investigated. We present the first model for testing drugs with targeted proresolution properties using quantifiable parameters of inflammatory resolution and homeostasis.
Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid-and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1 hi and Ly6c lo monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.oxylipins | resolution | monocyte | phagocytosis | epoxygenase M onocytes and monocyte-derived macrophages play a critical role in chronic inflammation, in part via the production and release of lipid mediators (1). One such lipid precursor, arachidonic acid, is metabolized into families of biologically active mediators by the cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) pathways (2, 3). CYPs metabolize arachidonic acid by: (i) an epoxygenase activity that catalyzes the conversion of arachidonic acid to epoxyeicosatrienoic acids (EETs); (ii) a lipoxygenase-like activity that metabolizes arachidonic acid to midchain hydroxyeicosatetraenoic acids (HETEs); and (iii) ω-and ω-1-hydroxylase activity, which produces ω-terminal HETEs (3). In addition to arachidonic acid, CYPs with epoxygenase activity can also metabolize alternative polyunsaturated fatty acids such as linoleic acid and docosahexaenoic acid into a series of products including epoxyoctadacamonoenoic acids (EpOMEs) and 19,20-epoxydocosapentaenoic acid (EpDPE), respectively, whose functions remain poorly understood (3-5).The main polyunsaturated fatty acid-metabolizing CYPs belong to the CYP2 family, in particular the CYP2J and CYP2C subfamilies (3, 4, 6, 7). Moreover, these CYP-lipid-metabolizing enzymes are the primary sources of eicosanoids in small blood vessels, the kidney, liver, lung, intestines, heart, and pancreas (3, 7). In most organs, EETs and related epoxygenase products are metabolically unstable and are rapidly metabolized. The major pathway that regulates EET metabolism is that catalyzed...
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