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Biomedical subjects

S Saadi

Publications and source records attributed to S Saadi.

At least 19 recordsLinked to original sources
PubMed2001

Platelet-mediated activation of endothelial cells: implications for the pathogenesis of transplant rejection.

BACKGROUND: Platelets exert their normal functions at sites of endothelial disruption by plugging discontinuities in blood vessels and secreting products that promote thrombosis, inflammation, and the healing of wounds. Whether platelets might induce these changes in xenograft blood vessels, leading to development of acute vascular rejection, has been uncertain. METHODS: To examine the role of human platelets in modulation of xenograft endothelium, pig endothelial cells were treated with human platelets. RESULTS: Treatment of quiescent porcine endothelial cells with human platelets modulated the endothelial cells. Whereas resting human platelets caused little change in normal porcine endothelial cells, platelets activated with small amounts of thrombin induced striking changes in the endothelial cells, including the induction of tissue factor activity, the expression of E-selectin, and the secretion of endothelin-1. These changes were induced, at least in part, by interleukin-1 (IL-1) associated with the platelet surface and were modified by the secretion of transforming growth factor-beta (TGF-beta). CONCLUSION: These findings may explain how the activation of platelets at an early point in the rejection of vascularized organ xenografts or in chronic diseases might contribute to thrombotic, ischemic, and inflammatory changes characteristic of an organ xenograft undergoing rejection.

Animals↗
PubMed2000

Endothelial cell activation by pore-forming structures: pivotal role for interleukin-1alpha.

BACKGROUND: Interaction of complement with endothelial cells (ECs) underlies the development of inflammation and coagulation in disease. Assembly of the membrane attack complex (MAC) of complement on EC membrane, like stimulation with cytokines, upregulates tissue factor and cyclooxygenase-2 but does so via the intermediary action of IL-1alpha. We asked whether the MAC activates porcine aortic and microvascular ECs in a global manner by this mechanism and whether this mechanism is used by membrane pore-forming structures. METHODS AND RESULTS: Exposure of ECs to complement caused upregulation of mRNAs for E-selectin, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, Ikappa-Balpha, interleukin (IL)-1alpha, IL-1beta, IL-8, and plasminogen activator inhibitor-1 over a period of 6 hours. The expression of these genes was not a primary response to stimulation, however, because IL-1 receptor antagonist inhibited expression of these genes. Activation of ECs by complement depended on the autocrine action of IL-1alpha, because complement-mediated EC activation was inhibited by anti-IL-1alpha antibodies. Melittin and mastoparan, amphiphilic pore-forming peptides like the MAC, induced E-selectin through intermediary action of IL-1. CONCLUSIONS: These findings suggest that transmembrane pore-forming proteins, as a class of molecules, activate ECs through the autocrine effects of IL-1alpha.

Animals↗
PubMed2000

Expression of tissue factor mRNA in cardiac xenografts: clues to the pathogenesis of acute vascular rejection.

BACKGROUND: Acute vascular rejection destroys vascularized xenografts over a period of hours to days and is now considered the major hurdle to the clinical application of xenotransplantation. The hallmark of acute vascular rejection is diffuse intravascular coagulation; however, the pathogenesis of coagulation is a matter of controversy. One line of evidence points to activated endothelial cells and another to activated inflammatory cells as a source of tissue factor and thus as a primary cause of this lesion. The distinction between the two mechanisms inducing coagulation in the xenograft provides an opportunity for specific intervention. METHODS: To explore these mechanisms, we studied the expression of tissue factor mRNA by in situ reverse transcriptase-polymerase chain reaction in relation to the histopathologic manifestations of acute vascular rejection in guinea pig hearts transplanted into rats treated by cobra venom factor to avoid the hyperacute rejection. RESULTS: Three hours after transplantation and before the deposition of fibrin, tissue factor mRNA was expressed in the endothelial cells lining small and medium blood vessels and in smooth muscle cells of guinea pig cardiac xenografts. Sixteen hours after transplantation, while rat tissue factor mRNA was expressed only in occasional infiltrating cells, cardiac xenografts showed prominent deposits of fibrin in small vessels. Maximum expression of tissue factor on rat infiltrating cells was observed 48 hr after transplantation. CONCLUSIONS: These results suggest that in acute vascular rejection, coagulation is initiated on the donor vascular system, while the procoagulant characteristics of infiltrating cells may reflect a response to tissue injury rather than a cause.

Acute Disease↗
PubMed1999

Dental knowledge and attitudes among Arab schoolteachers in northern Israel.

A representative random sample of 597 Arab school-teachers in northern Israel, was surveyed regarding sources and levels of knowledge and attitudes about dental caries prevention. Data were measured according to a self-administered questionnaire from a 91.4 per cent response rate. When ranking the effectiveness of different caries preventive measures teachers on average listed optimal water fluoridation as a lower priority compared to toothbrushing, dental visits, fluoride mouthrinses and eating fewer sweet products. Placing of fissure sealants was ranked as the second least effective caries preventive measure, with 39.6 per cent not knowing the effectiveness. Only 68.5 per cent of the school-teachers were aware of the anti-bacterial role of fluoride, and only a small minority knew of fluoride's potential in healing incipient caries. Teachers seemed less motivated to being involved in dental health school programmes which involved dedicating school time and their active involvement, such as fissure sealant programmes at school, supervision of brushing and flossing, and school mouthrinsing programmes. They revealed positive attitudes towards: informing parents about the importance of oral hygiene and teaching children about preventive dentistry. Teachers' main reported source of knowledge was the dental office. It is the responsibility of the dental profession to ensure that updated knowledge is correctly conveyed to schoolteachers, who are an important and potentially influential sector of dental health consumers and health education agents.

Adult↗
PubMed1999

Successful conservative treatment of severe renal candidosis with fungus balls.

Partial fungal obstruction of the renal collecting system is an unusual finding among infants that poses specific management problems. We report a patient with sepsis and fungal infection of the kidneys post surgery who presented with bilateral fungus balls and was successfully managed by conservative measures. Sonography is the imaging technique of choice in the diagnosis and follow-up of such patients. The need for prompt diagnosis in high-risk patients and the role of sonography are discussed.

Candidiasis↗
PubMed1999

Role of complement in xenotransplantation.

1. Xenotransplantation, or transplantation across species, leads to rejection, which destroys the xenograft within hours to days of transplantation. 2. Complement is a major barrier to xenotransplantation of vascularized organs and is believed to play an important role in the rejection process. 3. The present paper reviews three aspects of complement in xenotransplantation. These include the mechanisms and regulation of complement activation as well as tissue injury mediated by complement activation.

Animals↗
PubMed1998

Immunology of xenotransplantation.

The transplantation of tissues and organs between individuals of different species, that is, xenotransplantation, engenders a variety of immune responses. Xenogeneic immune responses mediated by naturally-occurring antibodies and complement lead to hyperacute and acute vascular rejection of vascularized organ grafts and may also cause vascular rejection of cell and tissue grafts. Under some circumstances, however, a vascularized organ graft may evade humoral rejection despite the presence of anti-donor antibodies in the circulation of the recipient; this condition is called accommodation. Xenogeneic immune responses mediated by T lymphocytes and natural killer cells may cause acute cellular rejection. The extent to which cellular rejection of xenografts resembles cellular rejection of allografts remains to be determined. New insights into the molecular mechanisms underlying the immune responses to xenotransplantation has shed light on the pathogenesis of immunological disease and has allowed the development of specific immunomodulatory strategies that may facilitate clinical application of xenotransplantation.

Animals↗
PubMed1997

Induction of procoagulant function in porcine endothelial cells by human natural killer cells.

NK cells may mediate effector functions other than target cell cytotoxicity. To explore such noncytotoxic effector mechanisms, we tested whether human PBL and purified NK (CD56+) cells might induce expression of tissue factor by cultured porcine aortic endothelial cells. Tissue factor is the major coagulation factor that binds to factor VIIa and initiates coagulation. The addition of freshly isolated NK cells but not T cells to endothelial cells resulted in the induction of tissue factor activity. NK-depleted (CD56-) effector cells did not induce tissue factor activity; however, the combination of CD56+ cells and NK-depleted cells induced tissue factor activity to the same extent as unseparated cells. PBL induced tissue factor mRNA in porcine endothelial cells and NK depletion resulted in a significant decrease of the induction. Induction of tissue factor activity in porcine endothelial cells by human NK cells required direct cell-to-cell contact, as transfer of supernatants from NK-endothelial cell cultures to secondary cultures did not induce tissue factor activity, and anti-LFA-1alpha Abs inhibited the induction of tissue factor activity. Induction of tissue factor activity in endothelial cells by NK cells may represent one of a variety of ways in which NK cells mediate noncytotoxic effects.

Animals↗
PubMed1997

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Lipid inflammatory mediators are thought to play a critical role in the pathogenesis of vascular injury. Among the events which might cause the synthesis of eicosanoids in blood vessels is activation of the complement. To evaluate how complement might influence eicosanoid metabolism, we investigated endothelial cells exposed to xenoreactive antibodies and complement, as might occur in rejecting xenografts where severe vascular injury is a typical feature. While resting porcine aortic endothelial cells released only prostaglandin (PG) I2, endothelial cells stimulated with xenoreactive antibodies and complement released PGE2 and thromboxane A2 (TXA2), in addition to increased amounts of PGI2. This alteration in eicosanoid metabolism was associated with induction of cyclooxygenase (Cox)-2 and thromboxane synthase, but not Cox-1. Unlike results seen in other systems, the upregulation of Cox-2 and the subsequent release of eicosanoids by endothelial cells was not directly induced by complement but rather required production of IL-1alpha, which acted on endothelial cells as an autocrine factor. Since eicosanoids have a potent effect on inflammation, vascular tone and platelet aggregation, we postulated that the abnormalities in eicosanoid release induced by xenoreactive antibodies and complement might provide one explanation for the vascular injury, focal ischemia, and thrombosis observed in acute vascular rejection and other vasculitides mediated by complement.

Animals↗
PubMed1997

Recent advances in the immunology of xenotransplantation.

The transplantation of tissue and organs between individuals of different species, that is xenotransplantation, engenders a variety of severe immune responses. Xenogeneic immune responses mediated by naturally occurring antibodies and complement lead to hyperacute and acute vascular rejection of vascularized organ grafts and may also cause vascular rejection of cell and tissue grafts. Under some circumstances, however, a vascularized organ graft may evade humoral rejection despite the presence of antidonor antibodies in the circulation of the recipient; this condition is called accommodation. Xenogeneic immune responses mediated by T-lymphocytes and natural killer cells may cause acute cellular rejection. The extent to which cellular rejection of xenografts resembles cellular rejection of allografts remains to be determined. New insights into the molecular mechanisms underlying the immune responses to xenotransplantation have shed new light on the pathogenesis of immunological disease and have allowed the development of specific immunomodulatory strategies that may facilitate clinical application of xenotransplantation.

Animals↗
PubMed1996

Differential expression of natural killer cell markers: human versus baboon.

The use of baboons as a model for the study of allo- and xenotransplantation has become increasingly important, but there are few studies on the basic immunological responses in baboons that might be relevant for a rejection reaction. In present study, the cell-surface phenotype, cytokine-induced activation and growth, and cytotoxicity of baboon and human natural killer (NK) and lymphokine-activated killer (LAK) cells were compared. A panel of murine monoclonal antibodies specific for human cell-surface markers expressed on lymphocytes was used to compare relevant baboon and human peripheral blood lymphocytes (PBL). Baboon PBL were 52.1+/-2.9% CD8+, 18.5+/-2.2% CD16+, 3.0+/-0.5% CD25+, and 5.5+/-1.8% CD69+. The corresponding proportions in humans were 23.8+/-7.1%, 12.8+/-3.2%, 4.5+/-1.0%, and 2.3+/-1.1%. In contrast to human PBL, less than 1% of baboon lymphocytes expressed CD56, CD57, and CD122 (interleukin [IL]-2Rbeta). Baboon lymphocytes showed NK cytotoxic activity against the human K562 and CEM cell lines, which was comparable to human NK activity. Depletion of baboon CD16+ or CD8+ cells led to dramatic decreases in NK cytotoxicity, and removal of both subsets completely abrogated NK activity. Incubation of baboon lymphocytes with human recombinant IL-2 for 1 week led to the appearance of CD56+ cells (11.3+/-2.8%). Most of the baboon CD56+ cells induced in culture were in S and G2 phases of cell cycle. Both baboon and human IL-2-activated lymphocytes were highly cytotoxic against the human LAK-sensitive cell line Daudi. Depletion of baboon CD8+ but not CD56+ cells significantly decreased LAK activity. These studies revealed differences in the NK system of humans and baboons that should be taken into consideration when analyzing immune responses to allo- and xenotransplantation in baboons.

Animals↗
PubMed1996

Human natural killer cells induce morphologic changes in porcine endothelial cell monolayers.

In this study, we have investigated the early in vitro effects of natural killer (NK) cells on porcine aortic endothelial cell (PAEC) monolayers. Incubation of effector cells containing about 70% CD56+ cells on PAEC monolayer led to time-dependent changes in PAEC monolayer morphology. As little as 20 min of incubation resulted in changes in PAEC shape and in the appearance of gaps between the cells. These effects have been observed for up to 6 hr, but not before 20 min or after 6 hr. When NK-depleted effector cells were used, no morphological changes were observed in comparison with the same effectors before depletion; if CD56+ cells were added back, the effects were comparable with those on nondepleted effector cells. There was no detectable NK cell-mediated cytolytic activity during the 1-6 hr of incubation of peripheral blood lymphocytes with PAEC monolayers. These data indicate that NK cells may participate in endothelial cell changes leading to xenograft rejection.

Animals↗
PubMed1996

Transplantation of discordant xenografts: a challenge revisited.

Six years ago, Jeffrey Platt and colleagues reviewed the biological hurdles to transplanting organs between species. The ensuing years have allowed the concepts advanced at that time to be tested leading to significant progress in understanding the immunology of xenotransplantation and in developing strategies for potential clinical application. Here, William Parker and colleagues review that progress.

Animals↗
PubMed1995

Complement-mediated regulation of tissue factor activity in endothelium.

Inflammation and immunity may be associated with endothelial cell (EC) injury and thrombus formation. We explored the mechanisms through which a humoral immune response directed against the endothelium might promote coagulation. Using the interaction of anti-EC antibodies and complement (C) with cultured EC as a model, we studied the expression and function of tissue factor, a cofactor for factor VIIa-mediated conversion of factor X to Xa. Exposure of EC to anti-EC antibodies and C in sublytic amounts stimulated the synthesis of tissue factor over a period of 16-42 h. Cell surface expression of tissue factor activity required activation of C and assembly of the membrane attack complex, because expression was inhibited by soluble CR1 and was not detected in the absence of C8. Elaboration of tissue factor messenger RNA was observed over a period of 8-30 h and required protein synthesis. Expression of tissue factor was not a direct consequence of the action of C on the EC but was a secondary response that required as an intermediate step the release of interleukin 1 alpha, an early product of the EC response to C activation. These findings suggest that, after the assembly of membrane attack complex on EC, the production of tissue factor and initiation of coagulation in a blood vessel depend on the production of interleukin 1 alpha and on its availability to stimulate affected EC.

Amino Acid Sequence↗
PubMed1995

Transient perturbation of endothelial integrity induced by natural antibodies and complement.

The barrier function of blood vessels is though to be regulated at least in part by endothelium. This concept is supported by the dramatic loss of barrier function occurring in the hyperacute rejection of vascularized grafts mediated by anti-endothelial cell (EC) antibodies and complement. In this process, the endothelium is not destroyed but instead loses the ability to retain blood cells and plasma proteins within capillaries. The noncytotoxic mechanism that allows this change in EC function has been unknown. Here we report that within 10 to 20 min of exposure to human xenoreactive natural antibodies and complement, porcine EC undergo alterations in cell shape and in the cytoskeleton that disrupt monolayer integrity and lead to formation of intercellular gaps. Gap formation is not associated with cell death but requires the complement complex C5b67. The gaps induced by anti-EC antibodies and complement are transient; gap closure requires formation of C5b-9 complexes on the cells and the rate of recovery depends on the release of cellular products into the medium. Preincubation of EC with dibutyryl cAMP (0.5 mM) prevents gap formation and disruption of the cytoskeleton caused by antibodies and complement. These results provide evidence that the integrity of endothelium is regulated by components of the complement system and suggest a mechanism that may explain the prominent loss of endothelial integrity seen in humoral immune responses.

Animals↗