Biomedical subjects

Paola Maderna

Publications and source records attributed to Paola Maderna.

8 recordsLinked to original sources

PubMed2006

Lipoxins and annexin-1: resolution of inflammation and regulation of phagocytosis of apoptotic cells.

Phagocytosis of apoptotic cells plays a pivotal role in developmental processes and in the resolution of inflammation. Failed or delayed clearance of apoptotic cells can result in chronic inflammation. Furthermore, clearance of apoptotic cells leads to release of anti-inflammatory cytokines. Recent evidence has shown that endogenous mediators can regulate such processes. In this article, we will review the recognition and signaling mechanisms involved in the phagocytosis of apoptotic cells as well as the role of endogenous compounds that play a relevant role in the modulation of inflammation. The first of these endogenous local mediators to be described are lipoxins (LXs). LXs and aspirin-triggered LXs (ATLs) are considered to act as "braking signals" in inflammation, limiting the entrance of leukocytes to the site of inflammation through inhibition of neutrophil and eosinophil trafficking. LXs are actively involved in resolution of inflammation, stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages. LXA4 and ATLs elicit cellular responses by interacting with a G protein -coupled receptor (ALXR) that is expressed in various cell types. ALXR, originally identified as a low-affinity N-formyl-methionyl-leucyl-phenylalanine receptor-like 1, can bind pleiotropic ligands, i.e., both lipid and peptides, including the glucocorticoid-inducible protein, annexin-1. Interestingly, a role for annexin-1 in phagocytosis has recently emerged. Understanding the role and mechanism of the powerful anti-inflammatory and proresolution actions of endogenous compounds can be a useful tool in the development of potential therapeutics in resolving inflammatory diseases.

Animals↗

PubMed2005

Modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide Ac(2-26).

Phagocytic clearance of apoptotic leukocytes plays an important role in the resolution of inflammation. The glucocorticoid-inducible protein annexin 1 and annexin 1-derived peptides show potent anti-inflammatory responses in acute and chronic inflammation. In this study, we report that the annexin 1-derived peptide (Ac(2-26)) significantly stimulates nonphlogistic phagocytosis of apoptotic polymorphonuclear leukocytes (PMNs) by human monocyte-derived macrophages (Mphi). Peptide Ac(2-26)-stimulated phagocytosis is accompanied by rearrangement of the Mphi actin cytoskeleton. To investigate the potential role of endogenous annexin on clearance of apoptotic cells, Mphi were cultured for 5 days in the presence of dexamethasone. Supernatants collected from dexamethasone-treated Mphi significantly enhanced the ability of naive Mphi to engulf apoptotic PMNs. This effect was blocked by an annexin blocking Ab, by immunodepletion of the supernatants, and by the formyl peptide receptor/lipoxin receptor antagonist Boc1. In addition, we show that bone marrow-derived Mphi from annexin 1-null mice present a 40% decreased phagocytosis of apoptotic PMNs compared with cells taken from littermate controls. In conclusion, these results emphasize the pivotal role of annexin 1 as mediator for clearance of apoptotic cells and expand its potential therapeutic role in controlling inflammatory diseases.

Actins↗

PubMed2005

Cytoskeletal reorganization and altered phagocytotic ability in primary cultures of rainbow trout hemopoietic tissue exposed to low-level ionizing radiation.

It has long been known that the hematopoietic tissue of mammals is one of the most radiosensitive tissues. In vitro studies on prawns have also shown that low doses of radiation have an extremely deleterious effect on cells cultured from this animal's blood-forming tissues. This raises questions about the relative effects of radiation in animals of different species. One of the most important aquatic animals, from both an economic and an ecological point of view, is the fish. With this in mind, primary cultures of the blood-forming tissues of rainbow trout were exposed to radiation followed by a morphological comparison between control and irradiated cultures. The cultured cells were characterized as macrophages after incubation with apoptotic human polymorphonuclear leukocytes and were classified as phagocytotic leukocytes. These cells were found in two morphological forms, stretched and rounded. It was shown that there was a commensurate increase in the number of stretched cells after irradiation. Radiation was also shown to cause a dose-dependent increase in the amounts of apoptosis in these cells over time. The phagocytotic efficacy of these cells was shown to inhibited by the exposure to low doses of radiation.

Animals↗

PubMed2004

Lipoxins: potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease.

Lipoxins are lipoxygenase-derived lipid mediators with both anti-inflammatory and proresolution properties that have been demonstrated in vivo and in vitro. The bioactivity profile of lipoxins in vitro suggests that they have therapeutic potential in acute renal failure and glomerulonephritis; predictions that have been borne out to date in experimental models of renal disease. We review recent developments on the molecular basis of lipoxin bioactions mediated through receptor crosstalk and the accumulating evidence that lipoxins may have potential as novel anti-inflammatory agents.

Animals↗

PubMed2003

Phagocytosis of apoptotic cells and the resolution of inflammation.

Clearance of apoptotic cells by phagocytic cells plays a significant role in the resolution of inflammation, protecting tissue from harmful exposure to the inflammatory and immunogenic contents of dying cells. Apoptosis induces cell surface changes that are important for recognition and engulfment of cells by phagocytes. These changes include alterations in surface sugars, externalization of phosphatidylserine and qualitative changes in the adhesion molecule ICAM-3. Several studies have contributed to clarify the role of the receptors on the surface of phagocytes that are involved in apoptotic cell clearance. The phagocytic removal of apoptotic cells does not elicit pro-inflammatory responses; in contrast, apoptotic cell engulfment appears to activate signals that suppress release of pro-inflammatory cytokines. Therefore, clearance of apoptotic leucocytes is implicated in the resolution of inflammation and mounting evidence suggests that defective clearance of apoptotic cells contributes to inflammatory and autoimmune diseases. Defining the ligands on apoptotic cells and the corresponding receptors on phagocytes with which they engage, is likely to lead to the development of novel anti-inflammatory pro-resolution drugs. In this article, we will review the recognition and signaling mechanisms involved in the phagocytosis of apoptotic cells as well as the role of endogenous compounds that play a relevant role in the modulation of inflammation. We will also discuss what is currently known about diseases that may reflect impaired phagocytosis and the consequences on inflammation and immune responses.

Apoptosis↗

PubMed2003

Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs.

OBJECTIVE: Tissue factor (TF) is the main activator of the coagulation cascade occurring in physiologic and pathologic conditions. Recent data suggest that human platelets might contain TF that is possibly derived from leukocytes. In this study, we investigated whether intraplatelet TF can be exposed on the membrane by platelet agonists. The modulation of this process by antiplatelet drugs has been evaluated as well. METHODS AND RESULTS: Flow cytometric analysis of unstimulated platelets showed a small amount of membrane-associated immunoreactive TF (irTF) in whole blood, platelet-rich plasma, and washed platelets isolated from healthy subjects. ADP, thrombin receptor-activating peptide, and epinephrine significantly increased functionally active, membrane-associated irTF. ADP induced irTF exposure in a concentration- and time-dependent fashion. Agonist-induced irTF expression was completely inhibited by iloprost but not by aspirin. Interestingly, glycoprotein IIb/IIIa antagonists did not inhibit but rather potentiated the stimulatory effect of ADP on platelet irTF expression. Real-time polymerase chain reaction experiments showed detectable amounts of TF mRNA in unstimulated platelets. CONCLUSIONS: These findings indicate that platelet agonists and antiplatelet drugs might modulate platelet-associated irTF expression. Regulated TF expression establishes the potential for a previously unrecognized role for platelets in sustaining thrombus formation and growth via coagulation-mediated mechanisms.

Antigens, Surface↗

PubMed2002

Lipoxins induce actin reorganization in monocytes and macrophages but not in neutrophils: differential involvement of rho GTPases.

Lipoxins (LXs) are endogenously produced eicosanoids that inhibit neutrophil trafficking and stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. In this study we assessed the effect of LXs on cell ultrastructure and actin reorganization in human leukocytes and investigated the signaling events that subserve LX bioactivity in this context. LXA(4) (10(-9) mol/L), the stable synthetic analogues 15-(R/S)-methyl-LXA(4) and 16-phenoxy-LXA(4) (10(-11) mol/L), but not the LX precursor 15-(S)-HETE, induced marked changes in ultrastructure and rearrangement of actin in monocytes and macrophages. In contrast, LXA(4) did not modify actin distribution in neutrophils under basal conditions and after stimulation with leukotriene B(4). Blockade of Rho kinases by the inhibitor Y-27632 prevented LXA(4)-triggered actin reorganization in macrophages. To investigate the role of the specific small GTPases in LX-induced actin rearrangement we used THP-1 cells differentiated to a macrophage-like phenotype. THP-1 cells stimulated with LXs, but not with 15-(S)-HETE, showed an increase in membrane-associated RhoA and Rac by immunoblotting. Additionally, a twofold increase in Rho activity was seen in response to LXA(4). LX-induced actin rearrangement and RhoA activation were inhibited by the cell permeable cAMP analogue 8-Br-cAMP, whereas Rp-cAMP, an inhibitor of protein kinase A, mimicked the effect of LXA(4). These data demonstrate that LXs stimulate RhoA- and Rac-dependent cytoskeleton reorganization, contributing to the potential role of LXs in the resolution of inflammation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMedDate not supplied

Taking insult from injury: lipoxins and lipoxin receptor agonists and phagocytosis of apoptotic cells.

Phagocytic clearance of apoptotic cells plays a pivotal role in the resolution of inflammation. Recent evidence has shown that such processes can be regulated by endogenous mediators, suggesting that specific mimetics may have therapeutic potential in chronic inflammation and autoimmune disorders. Here we review the mechanisms underlying recognition and engulfment of apoptotic cells and regulation of these processes by lipoxins and lipoxin receptor agonists.

Animals↗