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Mark W Geraci

Publications and source records attributed to Mark W Geraci.

34 records · Page 2Linked to original sources
PubMed2004

Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis.

Pigment epithelium-derived factor (PEDF) is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. PEDF expression was increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in IPF as a result of an imbalance between PEDF and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in IPF within the fibroblastic foci, and that within these areas PEDF was increased, whereas vascular endothelial growth factor was decreased. PEDF colocalized with the fibrogenic cytokine, transforming growth factor (TGF)-beta 1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-beta 1 might regulate PEDF expression. Using 3T3-L1 fibroblasts and human lung fibroblasts, we showed that PEDF was indeed a TGF-beta 1 target gene. Collectively, our findings implicate PEDF as a regulator of pulmonary angiogenesis and an important mediator in IPF.

Biopsy↗
PubMed2004

Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness.

The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I(2) (PGI(2)). Mice that overexpress PGI(2) synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI(2) receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI(2) is a potential therapeutic target in the treatment of RSV.

6-Ketoprostaglandin F1 alpha↗
PubMed2003

Expression of human herpesvirus 8 in primary pulmonary hypertension.

BACKGROUND: Severe pulmonary hypertension constitutes a group of diseases characterized by complex, lumen-occluding vascular lesions that develop in genetically susceptible persons. The only viral infection associated with severe pulmonary hypertension has been that due to human immunodeficiency virus type 1, but neither the viral genome nor viral antigens have been demonstrated in pathologic lesions. METHODS: We examined lung-tissue samples from 16 patients with sporadic primary pulmonary hypertension and 14 patients with secondary pulmonary hypertension for evidence of infection with human herpesvirus 8 (HHV-8). HHV-8 infection was ascertained immunohistochemically with use of an antibody directed against latency-associated nuclear antigen 1 (LANA-1), and a polymerase-chain-reaction (PCR) assay was performed on lung DNA to detect the viral cyclin gene of HHV-8. Sequence analysis was also performed. RESULTS: In lung tissue from 10 of 16 patients with primary pulmonary hypertension (62 percent), cells within the plexiform lesions as well as cells outside the lesions were positive for LANA-1 on immunohistochemical analysis. Tissue from the same 10 patients contained viral cyclin on PCR analysis. No LANA-1 was detected in lung tissue from patients with secondary pulmonary hypertension, although one such patient had PCR evidence of viral cyclin. Plexiform lesions from patients with primary pulmonary hypertension had a histologic and immunohistochemical resemblance to cutaneous Kaposi's sarcoma lesions. CONCLUSIONS: The spectrum of trigger factors and molecular mechanisms leading to severe pulmonary hypertension and the formation of plexiform lesions is apparently wide, including both genetic and epigenetic factors. Our data suggest that infection with the vasculotropic virus HHV-8 may have a pathogenetic role in primary pulmonary hypertension.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed2003

Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth.

PPARgamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPARgamma has been described and PPARgamma may function as a tumor suppressor gene, but little is known about the role of PPARgamma in vascular remodeling. One group of human diseases that shows impressive vascular remodeling exclusively in the lungs is the group of severe pulmonary hypertensive disorders, which is characterized by complex, endothelial cell-proliferative lesions of lung precapillary arterioles composed of clusters of phenotypically altered endothelial cells that occlude the vessel lumen and contribute to the elevation of the pulmonary arterial pressure and reduce local lung tissue blood flow. In the present study, we report the ubiquitous PPARgamma expression in normal lungs, and in contrast, a reduced lung tissue PPARgamma gene and protein expression in the lungs from patients with severe PH and loss of PPARgamma expression in their complex vascular lesions. We show that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARgamma (DN-PPARgamma ECV304) form sprouts when placed in matrigel and that DN-PPARgamma ECV304 cells, after tail vein injection in nude mice, form lumen-obliterating lung vascular lesions. We conclude that fluid shear stress decreases the expression of PPARgamma in endothelial cells and that loss of PPARgamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.

Animals↗
PubMed2003

Hypoxia induces different genes in the lungs of rats compared with mice.

Different animal species have a varying response to hypoxia. Mice develop less pulmonary artery thickening after chronic hypoxia exposure than rats. We hypothesized that the lung tissue gene expression pattern displayed in hypoxic rats would differ from that of hypoxic mice. We exposed Sprague-Dawley rats and C57BL/6 mice to both 1 and 3 wk of hypobaric hypoxia. Although both species developed pulmonary hypertension, mice showed less pulmonary vascular remodeling than rats. Microarray gene analysis demonstrated a distinct pattern of gene expression between mice and rats when exposed to hypoxic conditions. In addition, some genes appeared to be more responsive at an earlier time point of 1 wk of hypoxia. Hypoxic conditions in the rat induce genes involved in endothelial cell proliferation, repression of apoptosis, and vasodilation. Mice exposed to hypoxic conditions decrease the expression of genes involved in vasodilation and in endothelial cell proliferation. Although we cannot determine whether the differential expression of genes during chronic hypoxia is cause or consequence of the differential pulmonary vascular remodeling, we propose that a balance between over- and under-expression of a selective group of genes may be responsible for lung vascular remodeling and vascular tone control.

Animals↗
PubMed2003

Circulating endothelial cells in pulmonary hypertension.

The pulmonary endothelium plays a significant role in the pathobiology of Primary Pulmonary Hypertension. A number of diseases, related by a history of vascular injury, are associated with increased numbers of circulating endothelial cells (CECs). We hypothesized that patients with pulmonary hypertension would also have an increased number of circulating endothelial cells due to the high pressures and increased shear stress present within the pulmonary vasculature. We isolated the CECs from 14 patients with pulmonary hypertension, (5 primary and 11 secondary) and compared them to the cells from 12 normal controls. There was a significant increase in the number of CECs in peripheral blood in patients with both PPH and secondary pulmonary hypertension (SPH) when compared to normal volunteers (33.1 +/- 1.9 [PPH] and 27.2 +/- 6.9 [SPH] vs. 3.5 +/- 1.3 [controls], p < 0.001). The number of circulating endothelial cells in the patient's peripheral blood correlated significantly with the systolic, diastolic and mean pulmonary artery pressures of the individual. Approximately 50% of the CECs from patients with pulmonary hypertension expressed CD36, a marker of microvascular origin and 25% expressed E-selectin, a marker of endothelial cell activation. Although the origin of the CECs in patients with PH requires further investigation, one possible source is the pulmonary vasculature, and in patients with plexogenic pulmonary hypertension, the plexiform lesions. CECs may provide a non-invasive mean of accessing cells important to the pathobiology of severe pulmonary hypertension.

Adult↗
PubMed2002

Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer.

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I(2) (PGI(2), prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.

Animals↗
PubMed2002

TRAIL and inhibitors of apoptosis are opposing determinants for NF-kappaB-dependent, genotoxin-induced apoptosis of cancer cells.

Opposing pro- and anti-apoptotic actions of TRAIL and the inhibitors of apoptosis (IAPs) contribute to the cell's decision to survive or die. We demonstrate that in H157 human lung carcinoma cells, etoposide and doxorubicin induce the NF-kappaB-dependent expression of both pro- and anti-apoptotic proteins including TRAIL and its death receptor, DR5, and IAPs. Inhibition of NF-kappaB activation in H157 cells in response to genotoxin resulted in loss of cell surface expression of TRAIL and DR5, aggressive growth and chemotherapy resistance of tumors in nude mice. Similar to the paracrine TRAIL response in H157 cells, the sensitivity of normal lung and breast epithelium and carcinomas to undergo genotoxin-induced apoptosis correlates strongly with cell surface expression of TRAIL. Suppression of TRAIL signaling by expression of the TRAIL decoy receptor, DcR1, confers chemoresistance to cancer cells. These findings demonstrate that TRAIL signaling via its death receptors is a significant contributor to genotoxin-induced apoptosis in human epithelial carcinomas.

Apoptosis↗
PubMed2002

Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension.

Vascular endothelial growth factor (VEGF) plays a central role in the life and death of pulmonary vascular endothelial cells. Treatment of neonatal or adult rats with a VEGF receptor blocker destroys lung capillaries by inducing endothelial cell apoptosis and causes emphysema. Human lung tissue samples from patients with endstage emphysema have decreased levels of VEGF messenger RNA and protein and have decreased expression of kinase insert domain-containing receptor (VEGF receptor II). These decreases are associated with a high rate of alveolar septal cell apoptosis, indicating perhaps that decreased VEGF and kinase insert domain-containing receptor expression impairs endothelial cell survival in emphysematous lungs. Combination of VEGF receptor blockade with chronic hypoxia (3-wk exposure) results in obliteration of small precapillary pulmonary arteries by proliferating endothelial cells, severe pulmonary hypertension, and death caused by right-side heart failure. We propose that 1) VEGF receptor blockade causes endothelial cell apoptosis, 2) hypoxic vasoconstriction (shear stress) selects apoptosis-resistant endothelial cells that proliferate and obliterate the lumen, and 3) the vascular remodeling observed is relevant to the structural alterations that characterize severe pulmonary hypertension (including primary pulmonary hypertension) in humans. The endovascular cell growth in human disease and in our model exhibits some similarities with neoplastic cell growth. Chemotherapy strategies can now be employed in the animal model in an attempt to treat established vascular-obliterative lung disease.

Animals↗
PubMed2002

Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of different cancer cell types, suggesting a broad role for their cyclooxygenase (COX) targets and eicosanoid products in tumor cell growth. Sulindac sulfide, a COX inhibitor, inhibited the growth of non-small-cell lung cancers (NSCLC) both in soft agar and as xenografts in nude mice. Importantly, the concentration of sulindac sulfide required to inhibit NSCLC cell growth greatly exceeded the concentration required to inhibit prostaglandin (PG) E(2) synthesis in NSCLC cells, suggesting that NSAID inhibition of cell growth is mediated by additional targets distinct from COX. Both sulindac sulfide and ciglitazone, a defined peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, stimulated a promoter construct containing a PPAR response element linked to luciferase and potently inhibited NSCLC cell growth at similar concentrations, indicating a role for PPARgamma as a target of NSAID action in these cells. Overexpression of PPARgamma in NSCLC cells strongly inhibited the transformed growth properties of the cells, providing a molecular confirmation of the results obtained with the PPARgamma agonists. Increased expression of PPARgamma, as well as ciglitazone and sulindac sulfide induced expression of E-cadherin, which has been linked to increased differentiation of NSCLC. Despite the fact that SCLC cell lines expressed little or no cytosolic phospholipase A(2), COX-1, or COX-2, sulindac sulfide and PPARgamma agonists also inhibited the transformed growth of these lung cancer cells. We propose that PPARgamma serves as a target for NSAIDs that accounts for COX-independent inhibition of lung cancer cell growth.

Animals↗
PubMedDate not supplied

Prostaglandin E2 receptor subtype 2 (EP2) null mice are protected against murine lung tumorigenesis.

BACKGROUND: Manipulating prostaglandin (PG) production modulates tumor development. Elevated PGI2 production prevents murine lung cancer, while decreasing PGE2 content protects against colon cancer. PGE2 receptor subtype 2 (EP2) -deficient mice were hypothesized to be resistant to lung tumorigenesis. MATERIALS AND METHODS: EP2 null BALB/c mice and their wild-type littermates were exposed to an initiation-promotion carcinogenesis protocol and lung tumorigenesis was examined. Chronic lung inflammation was induced to determine whether EP2 ablation influenced inflammatory cell infiltration. RESULTS: Tumor multiplicity in EP2 null mice was 34% lower than in their wild-type littermates (21.9+/-3.0 vs. 14.5+/-2.9 tumors/mouse, p<0.001). The lung tumor burden, an indicator of growth rate, also declined (57%, p<0.05). All the mice exhibited similar inflammatory cell infiltration. CONCLUSION: PGE2, acting through EP2, enhanced lung tumorigenesis through a mechanism that may be distinct from its proinflammatory activity. Thus, EP2 is a potential target for novel chemoprevention strategies.

Animals↗