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Carlyne Cool

Publications and source records attributed to Carlyne Cool.

At least 19 recordsLinked to original sources
PubMed2006

Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension.

Severe pulmonary hypertension (SPH) is characterized by precapillary arteriolar lumen obliteration, dramatic right ventricular hypertrophy, and pericardial effusion. Our recently published rat model of SPH recapitulates major components of the human disease. We used this model to develop new treatment strategies for SPH. SPH in rats was induced using VEGF receptor blockade in combination with chronic hypoxia. A large variety of drugs used in this study, including anticancer drugs (cyclophosphamide and paclitaxel), the angiotensin-converting enzyme inhibitor lisinopril, the antiangiogenic agent thalidomide, and the peroxisome proliferator-actived receptor-gamma agonist PGJ2, failed to decrease mean pulmonary artery pressure (PAP) or right ventricular hypertrophy. In contrast, treatment of rats with established SPH with simvastatin markedly reduced mean PAP and right ventricular hypertrophy, and this reduction was associated with caspase-3 activation and pulmonary microvascular endothelial cell apoptosis. Simvastatin partially restored caveolin-1, caveolin-2, and phospho-caveolin expression in vessel walls. In rat primary pulmonary microvascular endothelial cells, simvastatin induced caspase 3 activation and Rac 1 expression while suppressing Rho A and attenuated levels of Akt and ERK phosphorylation. We conclude that simvastatin is effective in inducing apoptosis in hyperproliferative pulmonary vascular lesions and could be considered as a potential drug for treatment of human SPH.

Animals↗
PubMed2005

Pulmonary capillaritis in lung transplant recipients: treatment and effect on allograft function.

The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical syndrome characterized by dyspnea, hypoxemia, abnormal chest X-ray, and a decrease in forced expiratory volume in 1 second (FEV1); 25% presented with hemoptysis, and 18% with fulminant respiratory failure. Therapy with intravenous corticosteroids resulted in clinical improvement in 17 cases (43%). A response to plasmapheresis was seen in 12 (67%) of 18 cases refractory to corticosteroids. There were 5 deaths within 3 months of diagnosis. Nine (82%) of 11 lung transplant recipients who presented with capillaritis within 4 weeks post-transplant were alive at 1 year; all but 1 patient achieved expected percent predicted FEV1 values. Only 3 (14%) of 21 who presented with capillaritis > 1 month after transplant had a >20% decrease in the FEV1 after 12 months. These results suggest that post-transplant pulmonary capillaritis is (1) likely a form of acute allograft rejection clinically and histologically distinct from typical acute rejection, (2) less responsive to corticosteroid therapy than typical acute rejection, and (3) not associated with long-term adverse effects on allograft function.

Capillaries↗
PubMed2005

Low-voltage-activated (T-type) calcium channels control proliferation of human pulmonary artery myocytes.

While Ca2+ influx is essential for activation of the cell cycle machinery, the processes that regulate Ca2+ influx in this context have not been fully elucidated. Electrophysiological and molecular studies have identified multiple Ca2+ channel genes expressed in mammalian cells. Ca(v)3.x gene family members, encoding low voltage-activated (LVA) or T-type channels, were first identified in the central nervous system and subsequently in non-neuronal tissue. Reports of a potential role for T-type Ca2+ channels in controlling cell proliferation conflict. The present study tested the hypothesis that T-type Ca2+ channels, encoded by Ca(v)3.x genes, control pulmonary artery smooth muscle cell proliferation and cell cycle progression. Using quantitative RT/PCR, immunocytochemistry, and immunohistochemistry we found that Ca(v)3.1 was the predominant Ca(v)3.x channel expressed in early passage human pulmonary artery smooth muscle cells in vitro and in the media of human pulmonary arteries, in vivo. Selective blockade of Ca(v)3.1 expression with small interfering RNA (siRNA) and pharmacological blockade of T-type channels completely inhibited proliferation in response to 5% serum and prevented cell cycle entry. These studies establish that T-type voltage-operated Ca2+ channels are required for cell cycle progression and proliferation of human PA SMC.

Calcium Channels, T-Type↗
PubMed2005

Progression of asthma in childhood.

In general, asthma runs a variable course. However, there are children with asthma who are at risk for progressive disease that can lead to failure to attain peak lung growth and eventually can result in clinical and functional impairment. We present a case of a 14-year-old girl who has demonstrated a deterioration in lung function at least in the past 6 years. This has been associated with increasing medication requirements, including chronic oral corticosteroid and a steroid-sparing medication, the presence of comorbidities, and the occurrence of frequent exacerbations. The patient has evidence of airway inflammation and remodeling based on biomarkers and biopsy findings. It remains a challenge to determine patients at risk for irreversible airflow obstruction, presumably a result of airway remodeling. Histopathologic studies from biopsy samples provide the best evidence for this. However, bronchoscopy and biopsy require technical expertise and cannot be routinely used. Clinically, once a patient increases medication requirements, this should serve as a marker of disease progression. Biomarkers of airway inflammation such as exhaled nitric oxide, exhaled breath condensates, and induced sputum analysis may have the potential to monitor disease progression. Additional efforts are necessary to understand the mechanisms involved in this phenomenon and to discover specific modalities of treatment to target the structural changes of airway remodeling.

Adolescent↗
PubMed2005

Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy.

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.8 of untreated animals) and of right ventricular hypertrophy (Rv/Lv+S=0.55+/-0.02 versus 0.73+/-0.03 of untreated rats) and activation of Akt. Long-term stimulation with B9972 in our animal model of SPH resulted in decreased expression of the B2 receptor in lung vasculature. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels and by restoring caveolin-1 expression. B9972 also promoted eNOS activation. In vitro B9972 caused activation of caspase-3 as well as Erk and induction of prostacyclin production in rat pulmonary microvascular EC. Taken together our data suggest that a stable bradykinin B2 agonist B9972 demonstrates the capacity to reduce severe pulmonary hypertension, right ventricular hypertrophy and induce apoptosis of hyperproliferative cells in pre-capillary pulmonary arterioles.

Animals↗
PubMed2005

Radiologic and pathologic features of bronchiolitis.

OBJECTIVE: The purpose of this article is to describe and illustrate the clinical, pathologic, and imaging features of the inflammatory and fibrotic forms of bronchiolitis. The CT features presented in this article represent the typical features associated with each entity. CONCLUSION: Direct signs of bronchiolitis include centrilobular nodules and tree-in-bud pattern. Indirect signs include mosaic attenuation and air trapping. Although classic examples of each entity exist, there can be substantial overlap in the appearances, and distinguishing among these entities is not always possible. When high-resolution CT features overlap, clinical details will usually help to narrow the differential diagnosis.

Bronchiolitis↗
PubMed2004

Pathology of pulmonary hypertension.

This article briefly discusses the traditional concepts of severe pulmonary hypertension and then details how the concept of severe pulmonary hypertension has moved from a vasoconstrictive to an angioproliferative disorder.

Genetic Predisposition to Disease↗
PubMed2004

Lung inflation with direct injection of agarose: a technique for simultaneous molecular and morphometric measurements.

The usual methods for preparing lungs for morphologic study involve the instillation of fixatives that modifyproteins and RNA such that the tissue is unsuitable for molecular studies. To develop a technique suitable for molecular studies, pieces of adult rat lungs were infiltrated with agarose, glutaraldehyde, or paraformaldehyde and the consistency of alveolar inflation was compared to lungs inflated with 10% formalin. Only direct injection with 1% agarose resulted in comparable inflation of lung tissue and preserved RNA and protein. Thus, this technique enables simultaneous molecular and morphometric analysis of the lung on small pieces of lung tissue in heterogeneous lung diseases.

Animals↗
PubMed2003

Oxidative stress in severe pulmonary hypertension.

Severe pulmonary hypertension (PH) occurs in a primary or "unexplained" form and in a group of secondary forms associated with a number of diseases. Because the lung tissue from patients with severe PH demonstrates complex vascular lesions, which contain inflammatory cells, we wondered whether the lung tissue from patients with severe PH was "under oxidative stress." We used immunohistochemistry to localize nitrotyrosine and 8-hydroxy guanosine in the lung tissue sections from patients with primary and secondary PH. In some lung tissue extracts, the eicosanoid metabolites 5-oxo-eicosatetraenoic acid, leukotriene B4 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, and 15-HETE were measured using mass spectroscopy, and superoxide dismutase amount and activity were measured. Nitrotyrosine expression was ubiquitous in all PH lungs, and 5-oxo-eicosatetraenoic acid and HETE levels were elevated in the lungs of patients with severe PH but not in those lungs that were from the patients with severe PH treated chronically with prostacyclin. We conclude that indeed the lungs from patients with severe PH are under oxidative stress and that chronic prostacyclin infusion has an antiinflammatory effect on the lung tissue.

Arachidonic Acids↗
PubMed2003

Histopathology of severe childhood asthma: a case series.

BACKGROUND: To date, little has been published describing the pathology of severe childhood asthma. The currently accepted model of asthma holds that persistent airway inflammation leads to various symptoms of asthma, airway hyperresponsiveness, and airway remodeling that ultimately results in permanent loss of lung function. METHODS: Evaluation of six children referred to the National Jewish Medical and Research Center with difficult-to-control asthma, despite aggressive anti-inflammatory therapy, who underwent bronchoscopy with endobronchial biopsy to better characterize their disease. RESULTS: In every case, endobronchial biopsies revealed changes consistent with airway remodeling characterized by thickening of the basement membrane, smooth-muscle hypertrophy, with varying degrees of goblet-cell and submucous gland hyperplasia. The degree of subbasement membrane thickening did not appear to correlate with baseline FEV(1), ultimate FEV(1) following aggressive therapy, or lability in lung function. In five of six cases, there was minimal to no histologic evidence for airway inflammation with mild and patchy submucosal lymphocytic infiltration noted; eosinophils and neutrophils were not present. Further, the majority of the patients achieved normal FEV(1) values despite significant subbasement membrane thickening, counter to the current beliefs regarding airway remodeling and irreversible loss of lung function. CONCLUSIONS: This case report highlights some of the shortcomings of the current inflammatory paradigm for severe asthma. Despite little evidence of ongoing airway inflammation, many of the subjects displayed significant lung function lability. The lack of inflammation argues against steroid resistance at a cellular level, although it could be argued that inflammation may have been distal to the site sampled. Additionally, normal to nearly normal lung function was achieved despite the presence of significant remodeling. These findings suggest the need to look beyond inflammation to fully treat severe asthma and ultimately alter its progression.

Adolescent↗
PubMed2002

gamma-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth.

Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of beta-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that beta-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, gamma-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak gamma-catenin staining in approximately 30% of the specimens. Treatment of NSCLC cells expressing reduced gamma-catenin protein with 5-aza-2'-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased gamma-catenin protein content in NSCLC cells with low gamma-catenin expression. Significantly, the activity of a beta-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed gamma-catenin relative to those lines that highly expressed gamma-catenin. Moreover, transfection of these cells with a gamma-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that gamma-catenin can function as an inhibitor of beta-catenin/TCF-dependent gene transcription and highlights gamma-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis.

The role of nitric oxide (NO) in the host-defense against human tuberculosis (TB) is controversial. Although experimental evidence indicates that NO may play an important role in controlling TB, its expression in human tuberculous lungs has not been systematically characterized. We therefore investigated the expression of NO synthases (NOS) and of nitrotyrosine, the latter a marker of NO expression, in surgically resected lungs of eight patients with TB. Immunohistochemical and morphometric analyses revealed that, compared with control subjects, inducible NOS, endothelial NOS, and nitrotyrosine, but not neuronal NOS, were significantly elevated in the inflammatory zone of the tuberculous granulomas, and in the nongranulomatous pneumonitis zone. Tumor necrosis factor-alpha (TNF-alpha) was also significantly increased in tuberculous lungs and was principally localized to the necrotic, and to a lesser extent, the inflammatory and fibrotic areas of the granulomas. The NOS isoforms, nitrotyrosine, and TNF-alpha were expressed by the epithelioid macrophages and giant cells within the granulomas and in alveolar macrophages and epithelial cells in pneumonitis areas. This descriptive study provides evidence that in human TB, NOS isoenzymes and NO are present in specialized areas of the tuberculous granulomas; their precise role in human TB remains to be determined.

Epithelium↗
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

Lymphocyte activation in the lungs of SP-D null mice.

Surfactant protein D (SP-D) appears to play an important role in regulating local pulmonary inflammatory responses to pathogens. There is also in vitro evidence that SP-D may suppress local T cell responses. However, the role of SP-D in regulating T cell responses directly in the lung has not been previously evaluated in vivo. SP-D(-)(/-) mice demonstrate peribronchial and perivascular accumulations of lymphocytes. Therefore, we investigated the functional status and abundance of intrapulmonary lymphocytes in SP-D(-)(/-) mice. By morphometric analysis, SP-D(-)(/-) mice demonstrated increased numbers of airway- and vessel-associated lymphocytes without increases in interstitial lymphocytes. There was increased proliferative activity of lymphocytes isolated by enzymatic disassociation of minced lung. Flow cytometry was used to determine the number and functional activation status of intrapulmonary CD4(+) and CD8(+) T cells, as well as B cells and NK cells. Cytokine expression patterns in lung tissues were evaluated using RNase protection assays, reverse transcriptase/polymerase chain reaction, and enzyme-linked immunosorbent assay. There was marked T cell activation in the lungs of SP-D(-)(/-) mice, as reflected by an increased percentage of both CD4(+) and CD8(+) T cells expressing CD69 and CD25. BAL CD4 lymphocytes were increased and the fraction expressing CD69 was also increased. Although there were increases in BAL CD8 lymphocytes, apparent increases in CD69-positive CD8 lymphocytes did not reach statistical significance. In contrast, splenic T cells were not activated in SPD(-)(/-) mice. Of the proinflammatory cytokines evaluated, only interleukin (IL)-12 and IL-6 expression were consistently upregulated in the lungs of SPD(-)(/-) mice. Increased IL-2 expression was apparent but did not reach statistical significance. We conclude that the lack of local pulmonary production of SP-D leads to a state of persistent T cell activation, possibly in response to exogenous antigens. This study therefore provides further evidence of the important local immunoregulatory role of SP-D in vivo.

Animals↗
PubMedDate not supplied

Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features.

PURPOSE: The purpose of this study was to define the radiologic features of pulmonary neuroendocrine cell hyperplasia and correlate them with clinical findings. METHOD: Five women, ranging in age from 45 to 63 years, were diagnosed with pulmonary neuroendocrine cell hyperplasia. Two radiologists assessed the presence and extent of airway wall thickening, mosaic pattern, air trapping, ground-glass opacity, nodular opacity, and centrilobular opacity on high resolution CT. The CT findings were compared with physiologic data and histologic features. RESULTS: On CT scans, mosaic pattern was the predominant finding in all patients. The extent of mosaic pattern was correlated with the forced expiratory volume in 1 s/forced vital capacity ratio (r = 0.8508, p = 0.0317). Nodular lesions were noted in three patients. Airway walls were thickened in four patients. In one patient, ground-glass opacity and centrilobular opacity were also noted on high resolution CT. CONCLUSION: Pulmonary neuroendocrine cell hyperplasia is characterized by mosaic perfusion due to air trapping, airway wall thickening, and occasional small nodules on high resolution CT scans. The extent of mosaic perfusion correlates with physiologic evidence of airway obstruction.

Female↗