Biomedical subjects

E J Manseau

Publications and source records attributed to E J Manseau.

6 recordsLinked to original sources

PubMed1992

Vascular permeability factor mRNA and protein expression in human kidney.

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a potent microvascular permeability-enhancing mediator as well as a selective mitogen for vascular endothelium. In this study, in situ hybridization and immunohistochemistry co-localized VPF mRNA and protein to glomerular visceral epithelial cells in human kidneys. Northern analysis confirmed the presence of VPF mRNA of expected size. The finding of VPF in renal glomerular epithelium identifies a potent mediator of permeability and endothelial proliferation whose role in renal physiology and pathology requires investigation.

Amino Acid Sequence↗

PubMed1992

Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces.

Osteopontin, a glycoprotein with a glycine-arginine-glycine-aspartate-serine (GRGDS) cell-binding domain, has been described in bone and is also known to be expressed in other organs, particularly kidney. The goal of the present work was to define the distribution of osteopontin synthesis and deposition in a wide variety of normal adult human tissues using a multifaceted approach that included immunohistochemistry, in situ hybridization, and Northern analysis. Immunohistochemical studies have revealed the unexpected finding that osteopontin is deposited as a prominent layer at the luminal surfaces of specific populations of epithelial cells of the gastrointestinal tract, gall bladder, pancreas, urinary and reproductive tracts, lung, breast, salivary glands, and sweat glands. Northern analyses identified gallbladder as a major site of osteopontin gene transcription comparable in magnitude with that of kidney, and immunoblotting identified osteopontin in bile. In situ hybridization localized osteopontin gene transcripts predominantly to the epithelium of a variety of organs as well as to ganglion cells of bowel wall. Osteopontin of epithelial cell origin, like bone-derived osteopontin, promoted GRGDS-dependent cell spreading in attachment assays. We postulate that osteopontin secreted by epithelium binds integrins on luminal surfaces. Collectively, these findings suggest an important role for osteopontin on many luminal epithelial surfaces communicating with the external environment.

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PubMed1991

Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.

Vascular permeability factor (VPF) is a highly conserved 34-42-kD protein secreted by many tumor cells. Among the most potent vascular permeability-enhancing factors known, VPF is also a selective vascular endothelial cell mitogen, and therefore has been called vascular endothelial cell growth factor (VEGF). Our goal was to define the cellular sites of VPF (VEGF) synthesis and accumulation in tumors in vivo. Immunohistochemical studies were performed on solid and ascites guinea pig line 1 and line 10 bile duct carcinomas using antibodies directed against peptides synthesized to represent the NH2-terminal and internal sequences of VPF. These antibodies stained tumor cells and, uniformly and most intensely, the endothelium of immediately adjacent blood vessels, both preexisting and those newly induced by tumor angiogenesis. A similar pattern of VPF staining was observed in autochthonous human lymphoma. In situ hybridization demonstrated VPF mRNA in nearly all line 10 tumor cells but not in tumor blood vessels, indicating that immunohistochemical labeling of tumor vessels with antibodies to VPF peptides reflects uptake of VPF, not endogenous synthesis. VPF protein staining was evident in adjacent preexisting venules and small veins as early as 5 h after tumor transplant and plateaued at maximally intense levels in newly induced tumor vessels by approximately 5 d. VPF-stained vessels were also hyperpermeable to macromolecules as judged by their capacity to accumulate circulating colloidal carbon. In contrast, vessels more than approximately 0.5 mm distant from tumors were not hyperpermeable and did not exhibit immunohistochemical staining for VPF. Vessel staining disappeared within 24-48 h of tumor rejection. These studies indicate that VPF is synthesized by tumor cells in vivo and accumulates in nearby blood vessels, its target of action. Because leaky tumor vessels initiate a cascade of events, which include plasma extravasation and which lead ultimately to angiogenesis and tumor stroma formation, VPF may have a pivotal role in promoting tumor growth. Also, VPF immunostaining provides a new marker for tumor blood vessels that may be exploitable for tumor imaging or therapy.

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PubMed1979

Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response.

Recent reports of microvascular injury in delayed hypersensitivity skin reactions prompted us to reexamine the pathogenesis of first-set skin allograft rejection in man using morphologic techniques that allowed both extensive vessel sampling and unequivocal evaluation of microvascular endothelium. We here report that widespread microvascular damage is a characteristic, early consequence of the cellular immune response to first-set human skin allografts and is qualitatively similar to, but substantially more extensive than, that occurring in delayed hypersensitivity reactions. Microvascular damage in invariably preceded significant epithelial necrosis and affected initially and primarily those venules, arterioles, and small veins enveloped by lymphocytes. Vessels of both the allograft itself and the underlying graft bed (recipient tissue) were equally affected. These data suggest that endothelial cells of the microvasculature are the critical target of the immune response in first-set vascularized skin allograft rejection in man and that rejection can be attributed largely to ischemic infarction resulting from extensive microvascular damage. Other mechanisms, such as direct cellular contacts between infiltrating lymphocytes and epithelium, apparently played only a minor role. The findings presented here indicate that the rejection of first-set vascularized skin allografts, though induced by immunologically specific mechanisms, is primarily effected by final pathways that are relatively nonspecific and that may cause damage to both foreign and host vessels and cells. Rather than contradicting studies demonstrating the exquisite specificity of allograft rejection in other systems, these findings provide a further example of the heterogeneity of the cellular immune response. Recognition of the critical role of immunologically mediated microvascular injury may prove important both for an understanding of the biology of allograft rejection and for strategies aimed at prolonging allograft survival.

Antibody Formation↗

PubMed1979

Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression.

Line 1 and line 10 tumors became invested in a fibrin-gel cocoon within hours after transplantation to the subcutaneous spaces of unsensitized syngeneic inbred Sewall Wright strain 2 guinea pigs. The fibrin gel comprised more than 80% of the line 1 tumor mass and, after day 3, became organized and was subsequently replaced by fibrous connective tissue, which gave the tumor the appearance of a scirrhous carcinoma. A cellular infiltrate of lymphocytes and basophils developed at the periphery of line 1 tumors after day 8, and tumors regressed by day 13. The fibrin gel investing the highly malignant line 10 tumors accounted for less than 10% of the tumor mass and persisted without fibrous organization as a tumor grew progressively and invaded adjacent tissues. These data provide new and potentially important insights into the biology of solid tumor growth and the mechanisms of immunologic tumor rejection. Envelopment of tumors in a fibrin gel created an anatomic barrier separating the tumors from the host. Neovascularization mimicking that about line 1 and line 10 tumors was induced by sc fibrin implants; these data suggest that activation of the clotting and/or fibrinolytic systems by tumor cells may itself provide sufficient stimulus for induction of tumor angiogenesis without requiring a separate tumor angiogenesis factor. The scirrhous pattern of growth characteristic of line 1 tumors apparently was achieved by organization of an abundant fibrin gel. Line 1 tumor regression did not for the most part involve direct contacts between tumor cells and any type of inflammatory cell, including macrophages; rather, tumor destruction was effected by ischemic necrosis secondary to widespread microvascular injury. The mechanisms of such injury are uncertain, but tumor rejection was correlated with evidence of developing cellular immunity and anatomic associations between lymphocytes and myofibroblasts. Further experiments will be necessary before these findings can be generalized to other tumor systems.

Animals↗

PubMed1977

Systemic expression of cutaneous basophil hypersensitivity.

Guinea pigs primed for cutaneous basophil hypersensitivity (CBH) with several soluble proteins or with sheep erythrocytes developed a systemic, delayed-onset, maculopapular rash when challenged parenterally with specific antigen. The rash was most readily induced 5 to 7 days after immunization, at a time when local CBH skin test reactivity was also optimal. Miscroscopically, the rash resembled local CBH skin test reactions, being comprised of a papillary dermal infiltrate of basophils and lymphocytes and a striking dilatation and compaction of superficial venules. In addition to the systemic rash, animals expressing systemic CBH (SCBH) exhibited a striking eosinophilia at 24 hr which gave way to basophilia at 48 hr. Focal collections of eosinophils, and of smaller numbers of basophils, were found in the lungs and spleen; both eosinophils and basophils infiltrated the medulla of the thymus. Thus, basophil-rich infiltrations are favored in the skin even after systemic challenge with antigen and occur only to a much smaller extent in other organs where eosinophils may predominate. These differences in the response of various organs to challenge with parenteral antigen suggest that as yet unidentified local factors play a determinative role in regulating the inflammatory response. The pathogenesis of SCBH is not yet established, but it shares many of the properties of local CBH: histology, carrier specificity, development early after sensitization in the absence of detectable antibodies. Passive transfer has not been accomplished with serum alone but has been achieved irregularly with cells plus serum. SCBH may serve as a useful model for several disease states in man characterized by a systemic rash and eosinophilia, including certain types of drug reaction.

Animals↗