The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ethan A. Lerner - One of the best experts on this subject based on the ideXlab platform.
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Maxadilan the lutzomyia longipalpis vasodilator drives plasma leakage via pac1 cxcr1 2 pathway
Microvascular Research, 2012Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Ethan A. Lerner, Rafael S. Amendola, Mauro M. Teixeira, Christina Barjafidalgo, Julio ScharfsteinAbstract:Experiments were designed to determine if the vasodilatory peptides Maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5mm(2)) representative of the hamster cheek pouch microcirculation. Our studies showed that the sand fly vasodilator Maxadilan and PACAP-38 induced arteriolar dilation, leukocyte accumulation and plasma leakage in postcapillary venules. The recombinant mutant of Maxadilan M65 and an antagonist of CXCR1/2 receptors, reparixin, and an inhibitor of CD11b/CD18 up-regulation, ropivacaine, inhibited all these effects as induced by Maxadilan. Dextran sulfate, a complement inhibitor with heparin-like anti-inflammatory effects, inhibited plasma leakage and leukocyte accumulation but not arteriolar dilation as induced by Maxadilan and PACAP-38. In vitro studies with isolated human neutrophils showed that Maxadilan is a potent stimulator of neutrophil migration comparable with fMLP and leukotriene B(4) and that M65 and reparixin inhibited such migration. The data suggest that leukocyte accumulation and plasma leakage induced by Maxadilan involves a mechanism related to PAC1- and CXCR1/2-receptors on leukocytes and endothelial cells.
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Maxadilan, the Lutzomyia longipalpis vasodilator, drives plasma leakage via PAC1–CXCR1/2-pathway
Microvascular research, 2011Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Ethan A. Lerner, Rafael S. Amendola, Christina Barja-fidalgo, Mauro M. Teixeira, Julio ScharfsteinAbstract:Experiments were designed to determine if the vasodilatory peptides Maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5mm(2)) representative of the hamster cheek pouch microcirculation. Our studies showed that the sand fly vasodilator Maxadilan and PACAP-38 induced arteriolar dilation, leukocyte accumulation and plasma leakage in postcapillary venules. The recombinant mutant of Maxadilan M65 and an antagonist of CXCR1/2 receptors, reparixin, and an inhibitor of CD11b/CD18 up-regulation, ropivacaine, inhibited all these effects as induced by Maxadilan. Dextran sulfate, a complement inhibitor with heparin-like anti-inflammatory effects, inhibited plasma leakage and leukocyte accumulation but not arteriolar dilation as induced by Maxadilan and PACAP-38. In vitro studies with isolated human neutrophils showed that Maxadilan is a potent stimulator of neutrophil migration comparable with fMLP and leukotriene B(4) and that M65 and reparixin inhibited such migration. The data suggest that leukocyte accumulation and plasma leakage induced by Maxadilan involves a mechanism related to PAC1- and CXCR1/2-receptors on leukocytes and endothelial cells.
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Salivary gland homogenates of Lutzomyia longipalpis and its vasodilatory peptide Maxadilan cause plasma leakage via PAC1 receptor activation.
Journal of vascular research, 2009Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Sandra M.p. Oliveira, Ethan A. Lerner, Julio ScharfsteinAbstract:Objectives: Experiments were designed to determine if salivary gland homogenates (SGH) of the sand fly Lutzomyia longipalpis , the vasodilatory peptides Maxadilan
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Maxadilan, the PAC1 Receptor, and Leishmaniasis
Journal of Molecular Neuroscience, 2008Co-Authors: Vemuri B. Reddy, Ethan A. LernerAbstract:Maxadilan is a vasodilator peptide isolated from sand fly salivary glands. The vasodilator effects of Maxadilan are mediated by the PAC1 receptor, although Maxadilan and PACAP do not share sequence homology. Sand flies are the vector of the parasitic disease leishmaniasis. The peptide aids the sand fly in obtaining a blood meal while enhancing the infectivity of leishmania parasites transmitted by this arthropod vector. Aspects of Maxadilan, PAC1, and leishmaniasis are discussed.
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Maxadilan, a PAC1 receptor agonist from sand flies.
Peptides, 2007Co-Authors: Ethan A. Lerner, Aurel O. Iuga, Vemuri B. ReddyAbstract:In 1991, a potent 61 amino acid vasodilator peptide, named Maxadilan, was isolated from the salivary glands of the sand fly. Subsequently, it was shown that this peptide specifically and potently activated the mammalian PAC1 receptor, one of the three receptors for PACAP. These studies and the link between Maxadilan and leishmaniasis are discussed.
Richard G. Titus - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulatory effects of the Lutzomyia longipalpis salivary gland protein Maxadilan on mouse macrophages.
Infection and Immunity, 2007Co-Authors: Tess M. Brodie, Matthew C. Smith, Robin V. Morris, Richard G. TitusAbstract:Infection with Leishmania major is enhanced when the sand fly Lutzomyia longipalpis salivary peptide Maxadilan (MAX) is injected along with the parasite. Here we determined the effect that MAX has on the secretion of cytokines and nitric oxide (NO) and on parasite survival in macrophages (MΦs). The cytokines produced by MΦs can enhance a type 1 response, which will increase NO and the killing of intracellular pathogens such as L. major, or a type 2 response, leading to antibody production that is ineffective against intracellular pathogens such as L. major. A mouse macrophage cell line (RAW 264.7) was stimulated with various concentrations of MAX and lipopolysaccharide (LPS), and the supernatants were collected after 1, 2, and 3 days. Supernatants were assayed for interleukin-12p70 (IL-12p70), IL-10, IL-6, transforming growth factor β (TGF-β), NO, and tumor necrosis factor alpha (TNF-α). Our results indicate that the addition of MAX upregulates the cytokines associated with a type 2 response (IL-10, IL-6, and TGF-β) but downregulates type 1 cytokines (IL-12p70 and TNF-α) and NO. MAX was also added to L. major-infected mouse peritoneal exudate cells (PECs), and the parasite load increased significantly. The enhanced parasite load correlated with decreased NO production by PECs that were stimulated with LPS and gamma interferon in the presence of MAX. The ability of MAX to foster a type 2 response, to enhance parasite survival, and to decrease NO argues that MAX may be crucial for the early survival of Leishmania in the vertebrate host, and therefore, MAX holds considerable promise as an antigenic component for a vaccine against Leishmania.
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Immunomodulatory effects of Maxadilan and Phlebotomus papatasi sand fly salivary gland lysates on human primary in vitro immune responses.
Parasite immunology, 2003Co-Authors: Kathleen A. Rogers, Richard G. TitusAbstract:Leishmaniasis is a parasitic disease transmitted by the bite of Leishmania-infected sand flies. Here we show for the first time the ability of Maxadilan (Max), a vasodilatory peptide isolated from the sand fly Lutzomyia longipalpis, and salivary gland lysate (SGL) from Phlebotomus papatasi to decrease the secretion of Type 1 cytokines and to enhance the production of the Type 2 cytokine interleukin (IL)-6 by human peripheral blood mononuclear cells (PBMC) and monocytes. We found Max decreased the secretion of interferon (IFN)-gamma and IL-12p40 by PBMC and TNF-alpha by monocytes. SGL reduced the production of IFN-gamma by PBMC. In contrast, production of the Type 2 cytokine IL-6 was increased in Max or SGL-exposed cells. Finally, we determined that Max interacts with human cells through at least the pituitary adenylate cyclase activating polypeptide receptor. These results show that sand fly salivary gland components have an immunomodulatory effect on human cells, and this has important implications for the development of vaccines against leishmaniasis for humans.
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Maxadilan the vasodilator immunomodulator from lutzomyia longipalpis sand fly saliva stimulates haematopoiesis in mice
Parasite Immunology, 2002Co-Authors: Valerie O. Guilpin, Leanna Nosbisch, Christine Swardsonolver, Richard G. TitusAbstract:Protozoal parasites of the genus Leishmania are transmitted to their vertebrate host within the saliva of the sand fly during a blood meal. The saliva of the sand fly Lutzomyia longipalpis contains Maxadilan, a potent vasodilator and immunomodulator. Maxadilan has been shown to enhance the virulence of L. major in all strains of laboratory mice when injected along with the organism. Increased haematopoiesis has been associated with enhanced susceptibility to Leishmania organisms. Here, we show that Maxadilan alone stimulates bone marrow haematopoiesis through its ability to stimulate interleukin-6 production by bone marrow stromal cells. Moreover, these effects of Maxadilan are mediated through the interaction of Maxadilan with the pituitary adenylate cyclase activating polypeptide receptor. These data suggest that increasing haematopoiesis may be yet another way that Maxadilan enhances susceptibility of mice to Leishmania infection.
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Maxadilan, the vasodilator/immunomodulator from Lutzomyia longipalpis sand fly saliva, stimulates haematopoiesis in mice.
Parasite immunology, 2002Co-Authors: Valerie O. Guilpin, Christine J. Swardson-olver, Leanna Nosbisch, Richard G. TitusAbstract:Protozoal parasites of the genus Leishmania are transmitted to their vertebrate host within the saliva of the sand fly during a blood meal. The saliva of the sand fly Lutzomyia longipalpis contains Maxadilan, a potent vasodilator and immunomodulator. Maxadilan has been shown to enhance the virulence of L. major in all strains of laboratory mice when injected along with the organism. Increased haematopoiesis has been associated with enhanced susceptibility to Leishmania organisms. Here, we show that Maxadilan alone stimulates bone marrow haematopoiesis through its ability to stimulate interleukin-6 production by bone marrow stromal cells. Moreover, these effects of Maxadilan are mediated through the interaction of Maxadilan with the pituitary adenylate cyclase activating polypeptide receptor. These data suggest that increasing haematopoiesis may be yet another way that Maxadilan enhances susceptibility of mice to Leishmania infection.
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Sandfly Maxadilan Exacerbates Infection with Leishmania major and Vaccinating Against It Protects Against L. major Infection
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Robin V. Morris, Gregory C. Lanzaro, Charles B. Shoemaker, John R. David, Richard G. TitusAbstract:Bloodfeeding arthropods transmit many of the world’s most serious infectious diseases. Leishmania are transmitted to their mammalian hosts when an infected sandfly probes in the skin for a bloodmeal and injects the parasite mixed with its saliva. Arthropod saliva contains molecules that affect blood flow and modulate the immune response of the host. Indeed, sandfly saliva markedly enhances the infectivity of L. major for its host. If the salivary molecule(s) responsible for this phenomenon was identified, it might be possible to vaccinate the host against this molecule and thereby protect the host against infection with Leishmania . Such an approach represents a novel means of controlling arthropod-borne disease transmission. Here, we report that a single molecule, Maxadilan, in sandfly saliva can exacerbate infection with L. major to the same degree as whole saliva, and that vaccinating against Maxadilan protects mice against infection with L. major .
Gregory C. Lanzaro - One of the best experts on this subject based on the ideXlab platform.
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NEGATIVE EFFECT OF ANTIBODIES AGAINST Maxadilan ON THE FITNESS OF THE SAND FLY VECTOR OF AMERICAN VISCERAL LEISHMANIASIS
The American journal of tropical medicine and hygiene, 2004Co-Authors: Rania S. Milleron, Jose M C Ribeiro, Lynn Soong, Dia Elnaime, Gregory C. LanzaroAbstract:Lutzomyia longipalpis expresses a salivary protein called Maxadilan (MAX) that functions to dilate vertebrate blood vessels and thereby to facilitate the sand fly's acquisition of blood. We hypothesized that antibodies specific for one of many MAX variants would inhibit vasodilatory function of that variant. In vitro and in vivo experiments showed that antibodies against a specific MAX variant decreased vasodilatory function. More specifically, antibodies against MAX blocked vasodilation of a constricted rabbit aorta. Additionally, a strain of Lu. longipalpis, with a nearly uniform MAX genotype, obtained a larger blood meal from naive BALB/c mice compared with mice that were either immunized with a homologous MAX genotype or sensitized to bites of flies from the same strain. Those flies taking blood from mice sensitized by sand fly bites also laid significantly fewer eggs than when they took blood from naive mice. These results have potential epidemiologic importance in light of the potential use of MAX in a vaccine or as part of a diagnostic test because they imply that a uniform MAX genotype is selected against by the vertebrate host immune response and that antigenic diversity is selected for.
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ANTIGENIC DIVERSITY IN Maxadilan, A SALIVARY PROTEIN FROM THE SAND FLY VECTOR OF AMERICAN VISCERAL LEISHMANIASIS
The American journal of tropical medicine and hygiene, 2004Co-Authors: Rania S. Milleron, John Paul Mutebi, Sonia Valle, Alberto Montoya, Huaizhi Yin, Lynn Soong, Gregory C. LanzaroAbstract:The salivary protein Maxadilan (MAX) is a vasodilator and immunomodulator from the sand fly vector of the protozoan parasite Leishmania chagasi. Vaccinating BALB/c mice with sand fly salivary gland extracts or with MAX protects the host against L. major infection. Because of the potential use of MAX in an anti-Leishmania vaccine, we characterized the vertebrate host IgG response to MAX in the present study. Our immunochemical analysis indicated that antibodies to MAX were detected in BALB/c mice, as well as in pigs and humans, from a area in Nicaragua endemic for Lutzomyia longipalpis. Previous studies demonstrate that the MAX protein is polymorphic on the amino acid level. Our findings suggested that naturally occurring MAX variants were recognized specifically by the host immune system and antigenicity appeared to be associated with amino-acid sequence variability. Thus, antigenic diversity of MAX and possibly of other arthropod salivary proteins may dictate the development of vector-based vaccines(s).
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Antigenic diversity in Maxadilan, a salivary protein from the sand fly vector of American visceral leishmaniasis
2004Co-Authors: Gregory C. Lanzaro, Rania S. Milleron, John Paul Mutebi, Sonia Valle, Alberto Montoya, Huaizhi Yin, Lynn SoongAbstract:Antigenic diversity in Maxadilan, a salivary protein from the sand fly vector of visceral leishmaniasis Article in The American journal of tropical medicine and hygiene · April 200
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Sandfly Maxadilan Exacerbates Infection with Leishmania major and Vaccinating Against It Protects Against L. major Infection
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Robin V. Morris, Gregory C. Lanzaro, Charles B. Shoemaker, John R. David, Richard G. TitusAbstract:Bloodfeeding arthropods transmit many of the world’s most serious infectious diseases. Leishmania are transmitted to their mammalian hosts when an infected sandfly probes in the skin for a bloodmeal and injects the parasite mixed with its saliva. Arthropod saliva contains molecules that affect blood flow and modulate the immune response of the host. Indeed, sandfly saliva markedly enhances the infectivity of L. major for its host. If the salivary molecule(s) responsible for this phenomenon was identified, it might be possible to vaccinate the host against this molecule and thereby protect the host against infection with Leishmania . Such an approach represents a novel means of controlling arthropod-borne disease transmission. Here, we report that a single molecule, Maxadilan, in sandfly saliva can exacerbate infection with L. major to the same degree as whole saliva, and that vaccinating against Maxadilan protects mice against infection with L. major .
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Sibling species in the Lutzomyia longipalpis complex differ in levels of mRNA expression for the salivary peptide, Maxadilan
Insect molecular biology, 2000Co-Authors: Huaizhi Yin, Douglas E. Norris, Gregory C. LanzaroAbstract:Maxadilan is a small ( ∪ 7 kDa) protein found in the saliva of sand fly species in the Lutzomyia longipalpis complex, vectors of the parasite causing visceral leishmaniasis, Leishmania chagasi . It is a potent vasodilator and also has immunomodulatory affects. Maxadilan recovered from different sibling species of the Lu. longipalpis complex differ in amino acid content by as much as 23%, however all variants possess equivalent vasodilatory activity. Therefore, the dramatic differences in vasodilatory activity of the saliva from different sibling species is probably due to differences in the amounts of Maxadilan in their saliva. This is significant because it has been suggested that Maxadilan may influence the pathogenesis of leishmanial infections. In this study we measured the amount of Maxadilan messenger RNA (mRNA) per pair of salivary glands from individual sand flies by quantitative reverse transcription polymerase chain reaction (RT-PCR) using a competitive method. We report a method using the gene of interest, in this case Maxadilan, amplified by the PCR from genomic DNA, as a competitor in the quantitative RT-PCR, taking advantage of differences in the size of these products due to the presence of an intron. Significant differences in amounts of Maxadilan mRNA among colonies from Central and South America are described. We found a strong correlation between the amount of Maxadilan mRNA detected in salivary glands of different Lu. longipalpis sibling species and previously described differences in the size of erythemas produced by the bite of these species. Therefore, variation in the amount of mRNA suggests that differences in the vasodilatory properties of saliva among the different sibling species are the result of differences in the amount of Maxadilan present in the saliva and not differences in the potency of Maxadilan peptide variants. The geographical distribution of species with high or low levels of Maxadilan gene expression are concordant with the distribution of atypical cutaneous leishmaniasis resulting from infection with Le. chagasi , lending credence to earlier suggestions that Maxadilan may be involved with visceralization of this parasite.
Masahiro Tajima - One of the best experts on this subject based on the ideXlab platform.
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Maxadilan specifically interacts with pac1 receptor which is a dominant form of pacap vip family receptors in cultured rat cortical neurons
Brain Research, 2001Co-Authors: Ichiro Tatsuno, Daigaku Uchida, Tomoaki Tanaka, Aizan Hirai, Yasushi Saito, Osamu Moro, N Saeki, Masahiro TajimaAbstract:Abstract Maxadilan is a potent vasodilator peptide isolated from salivary gland extracts of the hematophagous sand fly. Recently, the possibility was demonstrated that Maxadilan binds to PAC1 receptor (PACAP, pituitary adenylate cyclase activating polypeptide type I receptor) in mammals. In the present study, we demonstrated that: (1) Maxadilan specifically binds to PAC1 receptor and stimulates cyclic AMP accumulation in a dose-dependent manner in CHO cells stably expressing PAC1 receptor, not VIP (vasoactive intestinal polypeptide) receptors; that (2) the deleted peptide (amino acid #24–42) of Maxadilan (termed max.d.4) also specifically binds to PAC1 receptor although max.d.4 inhibits cyclic AMP accumulation stimulated by both Maxadilan and PACAP; and that (3) max.d.4 completely blocks the cyclic AMP accumulation induced by VIP in cultured rat cortical neurons. The expression of specific PACAP receptors in cultured rat cortical neurons was further investigated by the reverse transcription-polymerase chain reaction technique, which showed the presence of mRNA coding for PAC1 receptor among PACAP/VIP family receptors. These data indicate that Maxadilan and max.d.4 represent important tools for clarifying the physiological role of PAC1 receptor, and that PAC1 receptor plays an important role in the regulation of the functions induced by PACAP in rat cultured cortical neurons.
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Functional Characterization of Structural Alterations in the Sequence of the Vasodilatory Peptide Maxadilan Yields a Pituitary Adenylate Cyclase-activating Peptide Type 1 Receptor-specific Antagonist *
The Journal of biological chemistry, 1999Co-Authors: Osamu Moro, Ethan A. Lerner, Sumiko Denda, Manami Ohnuma, Kaori Wakita, Masahiro TajimaAbstract:Maxadilan is a vasodilatory peptide derived from sand flies that is an agonist at the pituitary adenylate cyclase-activating peptide (PACAP) type 1 receptor. Surprisingly, Maxadilan does not share significant sequence homology with PACAP. To examine the relationship between structure and activity of Maxadilan, several amino acid substitutions and deletions were made in the peptide. These peptides were examined in vitro for binding to crude membranes derived from rabbit brain, a tissue that expresses PACAP type 1 receptors; and induction of cAMP was determined in PC12 cells, a line that expresses these receptors. The peptides were examined in vivo for their ability to induce erythema in rabbit skin. Substitution of the individual cysteines at positions 1 and 5 or deletion of this ring structure had little effect on activity. Substitution of either cysteine at position 14 or 51 eliminated activity. Deletion of the 19 amino acids between positions 24 and 42 resulted in a peptide with binding, but no functional activity. The capacity of this deletion mutant to interact with COS cells transfected with the PACAP type 1 receptor revealed that this peptide was a specific antagonist to the PACAP type 1 receptor.
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Immunomodulatory properties of Maxadilan, the vasodilator peptide from sand fly salivary gland extracts.
The American journal of tropical medicine and hygiene, 1996Co-Authors: Abrar A. Qureshi, Manami Ohnuma, Masahiro Tajima, Akihiko Asahina, Richard D. Granstein, Ethan A. LernerAbstract:Abstract Sand flies are the arthropod vector of leishmaniasis and salivary gland extracts from these flies exacerbate leishmaniasis in vivo. The mechanism of exacerbation appears to be due to immunomodulatory effects of the saliva on host immune function but the active component is unknown. The following studies reveal that Maxadilan, the vasodilatory peptide present in sand fly salivary gland extracts, has immunomodulatory properties. To examine the effect of Maxadilan on T cell proliferation, the peptide was added to murine spleen cells stimulated with either concanavalin A or plate-bound anti-T cell receptor antibody. Inhibition of proliferation was noted in a dose-dependent manner for both sets of experiments (P < 0.05). To examine the effect of Maxadilan on alloantigen presentation, the peptide was added to mixed lymphocyte and mixed epidermal cell lymphocyte reactions. Inhibition of proliferation was found in these culture systems. Maxadilan also inhibited the delayed-type hypersensitivity reaction in mice (P < 0.05). These observations suggest a role for Maxadilan in the pathogenesis of leishmaniasis since the peptide may inhibit the immune response at the site of parasite inoculation, allowing the infection to proceed.
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Structural characterization and location of disulphide linkages of a potent vasodilatory peptide, recombinant Maxadilan, by a multiple mass spectrometric approach.
Rapid communications in mass spectrometry : RCM, 1996Co-Authors: Seiichi Yoshida, Ethan A. Lerner, Tasuku Takamatsu, Sumiko Denda, Manami Ohnuma, Masahiro Tajima, Fujihiro KandaAbstract:A multiple mass spectrometric strategy using fast-atom bombardment (FAB) and matrix-assisted laser desorption/ionization (MALDI) has been used to confirm the sequence and to locate the disulfide linkages of recombinant Maxadilan (r-Maxadilan) (average molecular mass 7422.5 Da), a potent vasodilatory peptide from Lutzomyia longipalpis. MALDI measurements of intact r-Maxadilan, its reduced form and its pyridylethylated form (p-Maxadilan) indicated the presence of four Cys residues without major post-translational modifications. FAB and FAB-tandem mass spectrometry measurements of chymotryptic digests of p-Maxadilan were sufficient to map the primary structure of p-Maxadilan, though the complementary use of MALDI was necessary for complete mapping using Asp-N digestion due to a strong suppression observed in FAB. Assignment of the Cys-5-Cys-9 linkage was achieved by comparison of FAB mass spectra before and after reduction of tryptic digests of r-Maxadilan. Since the molecular weight of the peptide fragment containing the Cys-18-Cys 55 linkage is more than 4000, MALDI measurement was indispensable for assignment of this linkage. The results fully support the value of the multiple mass spectrometric strategy in the structural characterization of peptides and proteins.
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Receptors for the vasodilator Maxadilan are expressed on selected neural crest and smooth muscle-derived cells
Insect biochemistry and molecular biology, 1996Co-Authors: Osamu Moro, Masahiro Tajima, Ethan A. LernerAbstract:Abstract Maxadilan is a potent vasodilator peptide isolated from salivary glands of the blood feeding sand fly Lutzomyia longipalpis . The peptide relaxes rabbit aortic rings in an endothelium independent manner while elevating levels of cAMP and has been found to bind to membrane homogenates from brain. These studies on tissues have now been expanded with an examination of binding and signaling of Maxadilan to a number of established cell lines and primary cultures. The data reveal that Maxadilan binds to and stimulates the accumulation of cAMP in the rat pheochromocytoma line PC12 and the human neuroblastoma line NBfl. Accumulation of cAMP occurred in a transformed mouse pancreatic smooth muscle line (MILE) and primary rabbit aorta smooth muscle cells. The peptide did not bind to or induce cAMP formation in the rat thoracic aorta line L6. Scatchard analysis of binding to the PC12 and NBfl lines indicates that Maxadilan binds to a single class of high-affinity receptors. Similar pharmacologic actions and possible structural homologies between Maxadilan and calcitonin generelated peptide (CGRP) suggested the possibility that they shared receptors. However, competition studies and comparative second messenger analysis reveal that Maxadilan does not interact with receptors for CGRP, amylin or adrenomedullin and suggest that this peptide may bind to a novel receptor whose endogenous ligand remains unknown.
Julio Scharfstein - One of the best experts on this subject based on the ideXlab platform.
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Maxadilan the lutzomyia longipalpis vasodilator drives plasma leakage via pac1 cxcr1 2 pathway
Microvascular Research, 2012Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Ethan A. Lerner, Rafael S. Amendola, Mauro M. Teixeira, Christina Barjafidalgo, Julio ScharfsteinAbstract:Experiments were designed to determine if the vasodilatory peptides Maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5mm(2)) representative of the hamster cheek pouch microcirculation. Our studies showed that the sand fly vasodilator Maxadilan and PACAP-38 induced arteriolar dilation, leukocyte accumulation and plasma leakage in postcapillary venules. The recombinant mutant of Maxadilan M65 and an antagonist of CXCR1/2 receptors, reparixin, and an inhibitor of CD11b/CD18 up-regulation, ropivacaine, inhibited all these effects as induced by Maxadilan. Dextran sulfate, a complement inhibitor with heparin-like anti-inflammatory effects, inhibited plasma leakage and leukocyte accumulation but not arteriolar dilation as induced by Maxadilan and PACAP-38. In vitro studies with isolated human neutrophils showed that Maxadilan is a potent stimulator of neutrophil migration comparable with fMLP and leukotriene B(4) and that M65 and reparixin inhibited such migration. The data suggest that leukocyte accumulation and plasma leakage induced by Maxadilan involves a mechanism related to PAC1- and CXCR1/2-receptors on leukocytes and endothelial cells.
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Maxadilan, the Lutzomyia longipalpis vasodilator, drives plasma leakage via PAC1–CXCR1/2-pathway
Microvascular research, 2011Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Ethan A. Lerner, Rafael S. Amendola, Christina Barja-fidalgo, Mauro M. Teixeira, Julio ScharfsteinAbstract:Experiments were designed to determine if the vasodilatory peptides Maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage through activation of leukocytes and to what extent these effects could be due to PAC1 and CXCR1/2 receptor stimulation. Intravital microscopy of hamster cheek pouches utilizing FITC-dextran and rhodamine, respectively, as plasma and leukocyte markers was used to measure arteriolar diameter, plasma leakage and leukocyte accumulation in a selected area (5mm(2)) representative of the hamster cheek pouch microcirculation. Our studies showed that the sand fly vasodilator Maxadilan and PACAP-38 induced arteriolar dilation, leukocyte accumulation and plasma leakage in postcapillary venules. The recombinant mutant of Maxadilan M65 and an antagonist of CXCR1/2 receptors, reparixin, and an inhibitor of CD11b/CD18 up-regulation, ropivacaine, inhibited all these effects as induced by Maxadilan. Dextran sulfate, a complement inhibitor with heparin-like anti-inflammatory effects, inhibited plasma leakage and leukocyte accumulation but not arteriolar dilation as induced by Maxadilan and PACAP-38. In vitro studies with isolated human neutrophils showed that Maxadilan is a potent stimulator of neutrophil migration comparable with fMLP and leukotriene B(4) and that M65 and reparixin inhibited such migration. The data suggest that leukocyte accumulation and plasma leakage induced by Maxadilan involves a mechanism related to PAC1- and CXCR1/2-receptors on leukocytes and endothelial cells.
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Salivary gland homogenates of Lutzomyia longipalpis and its vasodilatory peptide Maxadilan cause plasma leakage via PAC1 receptor activation.
Journal of vascular research, 2009Co-Authors: Erik Svensjö, Elvira M. Saraiva, Marcelo T. Bozza, Sandra M.p. Oliveira, Ethan A. Lerner, Julio ScharfsteinAbstract:Objectives: Experiments were designed to determine if salivary gland homogenates (SGH) of the sand fly Lutzomyia longipalpis , the vasodilatory peptides Maxadilan