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H F Dvorak

Publications and source records attributed to H F Dvorak.

At least 37 records · Page 2Linked to original sources
PubMed1999

Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.

OBJECTIVE: The goal of these studies was to define the anatomic pathways by which circulating macromolecules extravasate from the hyperpermeable microvessels that supply tumors and from normal venules that have been rendered hyperpermeable by vasoactive mediators. METHODS: Extravasation pathways of circulating macromolecular tracers were followed by several morphological techniques: light and fluorescence microscopy, transmission electron microscopy of routine as well as ultrathin and serial sections, computer-assisted three-dimensional reconstructions, and morphometry. RESULTS AND DISCUSSION: Macromolecules extravasated across tumor microvessels or across normal venules rendered hyperpermeable by VPF/VEGF, histamine, or serotonin by three primary pathways: 1) Vesiculo-vacuolar organelles (VVOs), clusters of cytoplasmic vesicles and vacuoles that span endothelial cytoplasm from lumen to ablumen; 2) trans-endothelial cell (EC), pores, and 3) fenestrae. We also present data concerning the structure and function of VVOs as well as evidence that VVOs form as the result of linking together and fusion of caveolae-sized unit vesicles. Under suitable conditions VVOs also afforded a pathway for macromolecular transport in the reverse direction, i.e., from vascular ablumen to lumen. Finally, in addition to opening VVOs to the passage of macromolecules, mediators such as VPF/VEGF may also induce structural rearrangements of VVOs, transforming them into trans-EC pores or fenestrae.

Animals↗
PubMed1999

Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.

The generation of vascular stroma is essential for solid tumor growth and involves stimulatory and inhibiting factors as well as stromal components that regulate functions such as cellular adhesion, migration, and gene expression. In an effort to obtain a more integrated understanding of vascular stroma formation in breast carcinoma, we examined expression of the angiogenic factor vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow. We conclude that a distinct pattern of mRNA expression characterizes the generation of vascular stroma in breast cancer and that the formation of vascular stroma may play a role not only in growth of the primary tumor but also in invasion and metastasis.

Adenocarcinoma, Mucinous↗
PubMed1998

Mast cells can secrete vascular permeability factor/ vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression.

Vascular permeability factor/vascular endothelial cell growth factor (VPF/VEGF) can both potently enhance vascular permeability and induce proliferation of vascular endothelial cells. We report here that mouse or human mast cells can produce and secrete VPF/VEGF. Mouse mast cells release VPF/VEGF upon stimulation through Fcepsilon receptor I (FcepsilonRI) or c-kit, or after challenge with the protein kinase C activator, phorbol myristate acetate, or the calcium ionophore, A23187; such mast cells can rapidly release VPF/VEGF, apparently from a preformed pool, and can then sustain release by secreting newly synthesized protein. Notably, the Fc epsilonRI-dependent secretion of VPF/VEGF by either mouse or human mast cells can be significantly increased in cells which have undergone upregulation of Fc epsilonRI surface expression by a 4-d preincubation with immunoglobulin E. These findings establish that at least one cell type, the mast cell, can be stimulated to secrete VPF/VEGF upon immunologically specific activation via a member of the multichain immune recognition receptor family. Our observations also identify a new mechanism by which mast cells can contribute to enhanced vascular permeability and/or angiogenesis, in both allergic diseases and other settings.

Animals↗
PubMed1998

Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP.

Circulating leukocytes are thought to extravasate from venules through open interendothelial junctions. To test this paradigm, we injected N-formyl-methionyl-leucyl-phenylalanine (FMLP) intradermally in guinea pigs, harvesting tissue at 5-60 min. At FMLP-injected sites, venular endothelium developed increased surface wrinkling and variation in thickness. Marginating neutrophils formed contacts with endothelial cells and with other neutrophils, sometimes forming chains of linked leukocytes. Adherent neutrophils projected cytoplasmic processes into the underlying endothelium, especially at points of endothelial thinning. To determine the pathway by which neutrophils transmigrated endothelium, we prepared 27 sets of serial electron microscopic sections. Eleven of these encompassed in their entirety openings through which individual neutrophils traversed venular endothelium; in 10 of the 11 sets, neutrophils followed an entirely transendothelial cell course unrelated to interendothelial junctions, findings that were confirmed by computer-assisted three-dimensional reconstructions. Having crossed endothelium, neutrophils often paused before crossing the basal lamina and underlying pericytes that they also commonly traversed by a transcellular pathway. Thus, in response to FMLP, neutrophils emigrated from cutaneous venules by a transcellular route through both endothelial cells and pericytes. It remains to be determined whether these results can be extended to other inflammatory cells or stimuli or to other vascular beds.

Animals↗
PubMed1998

Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium.

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine and growth factor that has important roles in both pathological and physiological angiogenesis. VPF/VEGF induces vascular hyperpermeability, cell division, and other activities by interacting with two specific receptor tyrosine kinases, KDR/Flk-1 and Flt-1, that are selectively expressed on vascular endothelium. The signaling cascade that follows VPF/VEGF interaction with cultured endothelium is only partially understood but is known to result in increased intracellular calcium, activation of protein kinase C, and tyrosine phosphorylations of both receptors, phospholipase C-gamma (PLC-gamma) and phosphatidylinositol 3'-kinase. For many reasons, signaling events elicited in cultured endothelium may not mimic mediator effects on intact normal or tumor-induced microvessels in vivo. Therefore, we developed a system that would allow measurement of VPF/VEGF-induced signaling on intact microvessels. We used mouse mesentery, a tissue whose numerous microvessels are highly responsive to VPF/VEGF and that we found to express Flk-1 and Flt-1 selectively. At intervals after injecting VPF/VEGF i.p., mesenteries were harvested, extracted, and immunoprecipitated. Immunoblots confirmed that VPF/VEGF induced tyrosine phosphorylation of several proteins in mesenteric microvessels as in cultured endothelium: Flk-1; PLC-gamma; and mitogen-activated protein kinase. Similar phosphorylations were observed when mesentery was exposed to VPF/VEGF in vitro, or when mesenteries were harvested from mice bearing the mouse ovarian tumor ascites tumor, which itself secretes abundant VPF/VEGF. Other experiments further elucidated the VPF/VEGF signaling pathway, demonstrating phosphorylation of both PYK2 and focal adhesion kinase, activation of c-jun-NH2-kinase with phosphorylation of c-Jun, and an association between Flk-1 and PLC-gamma. In addition, we demonstrated translocation of mitogen-activated protein kinase to the cell nucleus in cultured endothelium. Taken together, these experiments describe a new model system with the potential for investigating signaling events in response to diverse mediators on intact microvessels in vivo and have further elucidated the VPF/VEGF signaling cascade.

Animals↗
PubMed1998

Secretion of vascular endothelial growth factor/vascular permeability factor from human luteinized granulosa cells is human chorionic gonadotrophin dependent.

Vascularization is a prominent event during corpus luteum formation, providing low density lipoproteins for steroid biosynthesis and enabling transport of secreted steroids. The process of vascularization is controlled by specific regulators. Vascular endothelial growth factor (VEGF), otherwise named vascular permeability factor (VPF), induces endothelial cell proliferation as well as angiogenesis in vivo and increases capillary permeability. Here we report the expression of VEGF/VPF mRNA by cultured human luteinized granulosa cells (GC) for at least 10 days. Without HCG VEGF/VPF expression declined after day 4 and by day 10 was reduced to approximately 30% of the value at day 4. However, after culture in the presence of 1 U/ml human chorionic gonadotrophin (HCG), expression of VEGF/VPF mRNA by GC was four times greater than control experiments by day 10, and increased 100% from day 4 to day 10. Simultaneously, HCG supplementation increased VEGF/VPF secretion by GC. Medium VEGF/VPF on day 3 was 13 pM without and 11 pM with HCG. Medium VEGF/VPF on day 10 was 6 pM without HCG and 29 pM with HCG. These results suggest that vascularization of the corpus luteum is induced by HCG-mediated effects of VEGF/VPF.

Adult↗
PubMed1998

Platelets exit venules by a transcellular pathway at sites of F-met peptide-induced acute inflammation in guinea pigs.

Platelets maintain the integrity of vascular endothelium, but also appear outside of blood vessels in pathological states such as acute inflammation. However, it is widely believed that platelets extravasate from blood vessels only as the result of endothelial injury and that, on contacting extravascular collagen, they undergo a morphologically defined activation sequence and release their granule contents. We here report that platelets may cross intact venular endothelium without exhibiting this release reaction or injury. Platelets became adherent to the luminal surface of venular endothelium within approximately 15 min of intradermal injection of 10(-5) M N-formyl-methionyl-leucyl-phenylalanine in guinea pig flank skin. Individual intact platelets were noted in large endothelial cell cytoplasmic vacuoles from which they subsequently migrated abluminally. They then crossed the vascular basal lamina and entered the dermis without exhibiting evidence of a release reaction. Serial electron-microscopic sections confirmed that the cytoplasmic vacuoles within which platelets crossed endothelial cells were independent of interendothelial cell junctions which remained normally closed. Platelets extended pseudopods and gave other evidence of cell motility. These findings require a paradigm shift in our thinking about platelet movement and functions.

Animals↗
PubMed1997

Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast.

BACKGROUND: Prior studies have indicated that ductal carcinoma in situ (DCIS) lesions are capable of inducing a vascular stroma. However, the mechanisms responsible for angiogenesis in DCIS currently are not defined. The goal of this study was to determine the relationship between the expression of the angiogenic cytokine vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), and angiogenesis in patients with DCIS. METHODS: Forty-six breast biopsies with DCIS were characterized with regard to histologic features on hematoxylin and eosin stained sections, and microvessel density and distribution using sections immunostained for factor VIII-related antigen. In addition, in situ hybridization was performed on formalin fixed, paraffin embedded sections using 35S labeled riboprobes specific for VPF/VEGF. RESULTS: VPF/VEGF expression by tumor cells in DCIS was greater than that observed in adjacent benign ductal or lobular epithelial cells in 96% of the evaluable cases. Moreover, the degree of VPF/VEGF mRNA expression was significantly associated with the degree of angiogenesis in these lesions. Among 22 cases with strong VPF/VEGF mRNA expression, the median microvessel count was 100 +/- 30.6 vessels/field. In contrast, among 24 cases with low level VPF/VEGF mRNA expression, the median microvessel count was 71 +/- 48.6 vessels/field (P = 0.04). In addition, high grade DCIS lesions more commonly were associated with strong VPF/VEGF mRNA expression than low grade lesions, but the results were not statistically significant. CONCLUSIONS: These findings suggest that VPF/VEGF is an important angiogenic factor in patients with DCIS.

Breast Neoplasms↗
PubMed1997

Reinterpretation of endothelial cell gaps induced by vasoactive mediators in guinea-pig, mouse and rat: many are transcellular pores.

1. In response to vascular permeabilizing agents, particulates circulating in the blood extravasate from venules through endothelial cell openings. These openings have been thought to be intercellular gaps though recently this view has been challenged. 2. To define the precise location of endothelial cell gaps, serial section electron microscopy and three-dimensional reconstructions were performed in skin and cremaster muscle of guinea-pigs, mice and rats injected locally with agents that enhance microvascular permeability: vascular permeability factor, histamine or serotonin. Ferritin and colloidal carbon were injected intravenously as soluble and particulate macromolecular tracers, respectively. 3. Both tracers extravasated from venules in response to all three permeability enhancing agents. The soluble plasma protein ferritin extravasated primarily by way of vesiculo-vacuolar organelles (VVOs), interconnected clusters of vesicles and vacuoles that traverse venular endothelium. In contrast, exogenous particulates (colloidal carbon) and endogenous particulates (erythrocytes, platelets) extravasated from plasma through transendothelial openings. 4. Serial electron microscopic sections and three-dimensional reconstructions demonstrated that eighty-nine of ninety-two openings were transendothelial pores, not intercellular gaps. Pore frequency increased 3- to 33-fold when carbon was used as tracer. 5. The results demonstrate that soluble and particulate tracers extravasate from venules by apparently different transcellular pathways in response to vasoactive mediators. However, some pores may derive from rearrangements of VVOs.

Animals↗
PubMed1997

The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways.

Mutation or loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is regularly found in sporadic renal cell carcinomas (RCC), well vascularized malignant tumors that characteristically overexpress vascular permeability factor/vascular endothelial growth factor (VPF/VEGF). The wild-type VHL (wt-VHL) gene product acts to suppress VPF/VEGF expression, which is overexpressed when wt-VHL is inactive. The present study investigated the pathways by which VHL regulates VPF/VEGF expression. We found that inhibition of protein kinase C (PKC) represses VPF/VEGF expression in RCC cells that regularly overexpress VPF/VEGF. The wt-VHL expressed by stably transfected RCC cells forms cytoplasmic complexes with two specific PKC isoforms, zeta and delta, and prevents their translocation to the cell membrane where they otherwise would engage in signaling steps that lead to VPF/VEGF overexpression. Other experiments implicated mitogen-activated protein kinase (MAPK) phosphorylation as a downstream step in PKC regulation of VPF/VEGF expression. Taken together, these data demonstrate that wt-VHL, by neutralizing PKC isoforms zeta and delta and thereby inhibiting MAPK activation, plays an important role in preventing aberrant VPF/VEGF overexpression and the angiogenesis that results from such overexpression.

Biological Transport↗
PubMed1997

Vascular permeability factor/vascular endothelial growth factor inhibits anchorage-disruption-induced apoptosis in microvessel endothelial cells by inducing scaffold formation.

Survival and proliferation of endothelial cells requires both growth factors and an appropriate extracellular matrix to which cells can attach. In the absence of either, endothelial cells rapidly undergo apoptosis. Thus, when human microvascular endothelial cells (HDMEC) are plated on a hydrophobic surface such as untreated polystyrene, they rapidly undergo apoptosis and die. The present study demonstrates that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), an endothelial cell-selective cytokine, inhibits apoptosis of HDMEC cultured on untreated polystyrene and induces these cells to adhere, spread, and proliferate. VPF/VEGF-induced HDMEC adhesion was time-dependent, required de novo protein synthesis, and was inhibited by a soluble RGD peptide but not by an inhibitor of collagen synthesis. Under the conditions of these experiments, VPF/VEGF downregulated expression of collagen IV and fibronectin but did not change collagen I mRNA levels. VPF/VEGF-induced HDMEC adhesion was inhibited by antibodies to alpha(v)beta5 and vitronectin but not by antibodies to alpha(v)beta3. Other endothelial growth factors and cytokines such as bFGF, HGF, and TGFbeta did not reproduce the VPF/VEGF effect. We suggest that VPF/VEGF induces endothelial cells to deposit a scaffolding (likely involving vitronectin) that allows them to attach to and proliferate on an otherwise nonsupportive surface (hydrophobic polystyrene) and in this manner serves as both a survival factor and a growth factor.

Actin Cytoskeleton↗
PubMed1997

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) delays and induces escape from senescence in human dermal microvascular endothelial cells.

Like most other normal cells, human endothelial cells possess a limited replicative life span, and, after multiple passages in vitro, develop an arrest in cell division referred to as replicative senescence. For many cell types senescence can be delayed by oncogenes or tumor suppressor genes or prevented altogether by malignant transformation; however, once developed, senescence has been regarded as irreversible. We now report that a cytokine, vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), significantly delays senescence in human dermal microvascular endothelial cells (HDMEC). Typically, VPF/VEGF-treated HDMEC could be cultured for at least 15-20 more population doublings (PD) than control cells. Protection from senescence was reversible in that subsequent withdrawal of VPF/VEGF returned cells to the senescent phenotype. Expression of several cell cycle-related genes (p21, p16 and p27) was significantly reduced in VPF/VEGF-treated cells but p53 expression was not significantly altered. Of particular importance, VPF/VEGF was able to rescue senescent HDMEC, restoring them to proliferation, to a more normal morphology, and to reduced expression of a senescence marker, neutral beta-galactosidase. Taken together, VPF/VEGF delayed the onset of senescence and also reversed senescence in microvascular endothelial cells without inducing cell transformation.

Brain-Derived Neurotrophic Factor↗
PubMed1997

Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine.

VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the endothelial cells lining nearby microvessels to proliferate, to migrate and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular endothelial cells hyperpermeable so that they spill plasma proteins into the extravascular space, leading to profound alterations in the extracellular matrix that favor angiogenesis. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of endothelial cell division and new blood vessel formation. It would seem, therefore, that tumors have made use of fundamental pathways that developed in multicellular organisms for purposes of tissue defense, renewal and repair. VPF/VEGF, therefore, has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important--perhaps essential--elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in sub-toxic concentrations that are more than sufficient to induce angiogenesis (Connolly et al., 1989a). Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating VPF/VEGF expression. In fact, there are already clear example of this. A number of putative angiogenic factors including small molecules (e.g. prostaglandins, adenosine) as well as many cytokines (e.g. TGF-alpha, bFGF, TGF-beta, TNF-alpha, KGF, PDGF) have all been shown to upregulate VPF/VEGF expression. Further studies that elucidate the crosstalk among various angiogenic factors are likely to contribute significantly to a better understanding of the mechanisms by which new blood vessels are formed in health and in disease.

Adult↗
PubMed1997

Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptors in human skin.

Tissue hypoxia is a characteristic feature of malignant tumors and healing wounds, conditions that are associated with angiogenesis and with increased expression of vascular permeability factor (VPF; also called vascular endothelial growth factor, VEGF), a selective endothelial cell mitogen inducing microvascular hyperpermeability in vivo. We investigated the regulation of VPF/VEGF and its receptors by tissue hypoxia in normal human skin explants and in cultured skin cells in vitro. VPF/VEGF mRNA expression was dramatically upregulated in epidermal keratinocytes, dermal fibroblasts, and dermal microvessels after 24 h of skin organ culture. Hypoxia also enhanced the expression of VPF/VEGF in cultured epidermal keratinocytes and dermal microvascular endothelial cells (predominantly VPF/VEGF121 and VPF/VEGF165) and in dermal fibroblasts (additional upregulation of VPF/VEGF189). The expression of the VPF/VEGF receptor Flt-1 was selectively induced on dermal microvessels in skin explant cultures and in dermal endothelial cell monolayer cultures under hypoxic conditions. In contrast, the KDR receptor was downregulated by hypoxia. These results suggest that hypoxia likely regulates cutaneous angiogenesis and microvascular permeability by two distinct mechanisms: (i) Induction of VPF/VEGF in epithelial and mesenchymal cells, including endothelial cells. (ii) Differential modulation of VPF/VEGF receptor expression by microvascular endothelial cells. These mechanisms may be of importance in the pathogenesis of healing wounds and some malignant tumors that are commonly characterized by hypoxia and overexpression of VPF/VEGF.

Cells, Cultured↗
PubMed1997

Ultrastructural immunogold localization of osteopontin in human gastric mucosa.

We performed ultrastructural immunogold localization of osteopontin in the mucosa of human stomach. This adhesive glycoprotein was present in mucous and chief cells of the epithelial layer and in macrophages in the lamina propria. Parietal and endocrine cells of the epithelial layer and mast cells and plasma cells in the lamina propria did not contain osteopontin, serving as internal negative controls. Subcellular localizations of osteopontin included secretory granules and synthetic organelles in mucous and chief cells and phagolysosomes in macrophages. Extracellular concentrations of osteopontin were present in the glycocalyx and in an electron-lucent band between epithelial surface cells and the gastric lumen. Paracellular edema between the epithelium of the same cells was devoid of osteopontin. Immunogold localization of pepsinogen II was done to identify cells with mixed granule populations and contents of multicompartmental secretory granules. These studies revealed mucous cell granules and chief cell granules, each containing compartmentalized storage products, which included osteopontin and mucigen in mucous cells and osteopontin and pepsinogen II in chief cells. Cytochemical controls for the immunogold localizations were negative. The subcellular distribution of osteopontin in human gastric mucosa suggests possible roles for this glycoprotein in barrier function, host defense, and/or secretion.

Cell Adhesion↗
PubMed1997

Angiogenesis: a dynamic balance of stimulators and inhibitors.

Angiogenesis, the formation of new blood vessels from a pre-existing vasculature, is tightly regulated in normal adults. Under physiological circumstances, angiogenesis occurs in only a few instances; e.g., the female reproductive system in response to ovulation or gestation, the normal hair cycle, etc. In these examples, growth of new capillaries is tightly controlled by an interplay of growth regulatory proteins which act either to stimulate or to inhibit blood vessel growth. Normally, the balance between these forces is tipped in favor of inhibition and consequently capillary growth is restrained. Under certain pathological circumstances, however, local inhibitory controls are unable to restrain the increased activity of angiogenic inducers. Thus, in wound healing, inflammation and tumors, to name just a few examples, angiogenesis is integral to the pathology, engendering the hope that these pathological entities could be regulated by pharmacological and/or genetic suppression (or enhancement) of blood vessel growth. This hope, in turn, has fostered interest in the molecular mechanisms that regulate angiogenesis. In this chapter, we have reviewed the current literature regarding some angiogenic stimulators and inhibitors, emphasizing vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), as a major angiogenic inducer, and thrombospondin (TSP) as the best known example of a natural inhibitor of vessel growth.

Cytokines↗
PubMed1997

Osteopontin is strongly expressed by histiocytes in granulomas of diverse etiology.

Granulomatous inflammation is associated with a variety of important pathologic conditions. Osteopontin (OPN), a ligand for the alpha v beta 3 integrin, is a secreted glycoprotein with a glycine-arginine-glycine-aspartate-serine cell-binding domain. In this study, we examined expression of OPN in 22 cases of granulomatous inflammation including cases of sarcoidosis, granulomatous temporal arteritis, histoplasmosis, rheumatoid nodule, granuloma annulare, erythema nodosum, granulomatous gastritis, foreign body giant-cell granulomatous reactions, and lipogranulomas. Strong expression of OPN mRNA and protein was seen in the epithelioid histiocytes and multinucleate histiocytic giant cells in granulomas by in situ hybridization and immunostaining. OPN may play an important role in granulomatous inflammation through the regulation of processes such as histiocyte migration, cell adhesion, and cellular functions including phagocytosis.

Animals↗