Abstract. Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA 4 stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (M) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA 4 , LXB 4 , the aspirin-triggered LX (ATL) epimer, 15-epi-LXB 4 , and a stable synthetic analogue 15(R/S)-methyl-LXA 4 stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA 4 , LXB 4 , 15(R/S)-methyl-LXA 4 , and 15-epi-LXB 4 of 2.5 to 10 g/kg. Non-phlogistic LX-stimulated phagocytosis by M was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-␤ 1 (TGF-␤ 1 ). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M to ␤1,3-glucan, suggesting a novel M-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA 4 receptor (MYFINITL and LESI-FRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-␤ 1 release. These data provide the first demonstration that LXA 4 , LXB 4 , ATL, and LX stable analogues rapidly promote M phagocytosis of PMN in vivo and support a role for LX as rapidly acting, proresolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.Rapid, efficient and tightly regulated recruitment and clearance of polymorphonuclear neutrophil (PMN) at sites of inflammation are essential components of effective host defense. Evidence from in vitro models and from histopathology suggests that tissue damage mediated by PMN is limited by apoptosis and subsequent phagocytosis of the apoptotic PMN by macrophages (M) and "nonprofessional" phagocytes (1). A direct role for PMN in tissue injury in inflammation and ischemia reperfusion injury of the kidney and other organs is well established (2). Impaired clearance of apoptotic cells by M has been implicated in the pathogenesis of chronic inflammatory conditions, including glomerulonehritis (GN) and systemic lupus erythematosus (SLE) (3). The endogenous signals that promote clearance of apoptotic PMN from an inflammatory focus are still being defined. By dissecting out the mediator systems that regulate this process, it may be possible to design new pro-resolution strategies for inflammatory diseases.Lipoxins (LX), an acronym for...

Tissue transglutaminase is a calcium-dependent enzyme that catalyzes the cross-linking of polypeptide chains, including those of extracellular matrix (ECM) proteins, through the formation of ⑀ -( ␥ -glutamyl) lysine bonds. This crosslinking leads to the formation of protein polymers that are highly resistant to degradation. As a consequence, the enzyme has been implicated in the deposition of ECM protein in fibrotic diseases such as pulmonary fibrosis and atherosclerosis.In this study, we have investigated the involvement of tissue transglutaminase in the development of kidney fibrosis in adult male Wistar rats submitted to subtotal nephrectomy (SNx). Groups of six rats were killed on days 7, 30, 90, and 120 after SNx. As previously described, these rats developed progressive glomerulosclerosis and tubulo-interstitial fibrosis. The tissue level of ⑀ -( ␥ -glutamyl) lysine cross-link (as determined by exhaustive proteolytic digestion followed by cation exchange chromatography) increased from 3. 47

Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11β-hydroxysteroid dehydrogenases (11β-HSDs) modulates cellular steroid action. 11β-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11β-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11β-HSD1, as 11β-HSD1 mRNA, but not 11β-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1−/− macrophages, and carbenoxolone, an 11β-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1−/− mice. These data point to an early role for 11β-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.

We conclude that IFN-gamma, administered at a dose of 400 units/day, has a strong inhibitory effect on myofibroblasts and that as a possible result of this action, renal fibrosis is reduced and renal function is preserved in the rat SNx model. The IFN-gamma renoprotective effect lasted only for the extent of its administration and subsided when discontinued.