Biomedical subjects
E M Wagner
Publications and source records attributed to E M Wagner.
Absent or low expression of the zeta chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma.
Immunohistology for expression of the CD3zeta and CD3epsilon chains in TIL was performed in 138 paraffin-embedded primary oral squamous cell carcinoma tissues and 10 nontumor, inflammatory lesions. Semiquantitative analysis of the staining intensity for zeta chain expression and number of zeta chain expression-positive cells distinguished tumors with absent or low zeta expression (42 of 132) from those with normal zeta expression (90 of 132). Zeta chain expression was inversely correlated with the tumor stage. Survival was significantly lower in patients whose TIL had absent or low zeta expression, controlling for stage (P = 0.003) and lymph node status (P = 0.0005). The prognostic value of zeta chain was restricted to patients with stage III or IV tumors (P = 0.003). The data indicate that absent or decreased zeta expression in TIL combined with tumor stage or nodal status defines a group of patients with oral squamous cell carcinoma who have an extremely poor prognosis.
Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice.
The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.
Microsphere-induced bronchial artery vasodilation: role of adenosine, prostacyclin, and nitric oxide.
We previously found that injection of 15-micron microspheres into the bronchial artery of sheep decreased bronchial artery resistance. This effect was inhibited partially by indomethacin or 8-phenyltheophylline, suggesting that microspheres caused release of a dilating prostaglandin and adenosine. To identify the prostaglandin and confirm adenosine release, we perfused the bronchial artery in anesthetized sheep. In 12 sheep, bronchial artery blood samples were obtained before and after the infusion of 1 x 10(6) microspheres or microsphere diluent into the bronchial artery. Microspheres, but not diluent, decreased bronchial artery resistance by 40% and increased bronchial artery plasma 6-ketoprostaglandin F1 alpha (194.7 +/- 45.0 to 496.5 +/- 101.3 pg/ml), the stable metabolite of prostacyclin, and prostaglandin (PG) F2 alpha (28.1 +/- 4.4 to 46.2 +/- 9.7 pg/ml). There were no changes in PGD2, PGE2, thromboxane B2, adenosine, inosine, or hypoxanthine. Pretreatment with dipyridamole, an adenosine uptake inhibitor, did not affect bronchial artery nucleoside concentrations (n = 7). Microsphere-induced vasodilation was not enhanced by dipyridamole (n = 9) and was not inhibited by either the adenosine receptor antagonist xanthine amine congener (n = 4) or the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (n = 8). These results do not support a role for either adenosine or NO and suggest that microspheres caused bronchial artery vasodilation through release of prostacylin and an unidentified vasodilator.
Bronchial vascular contribution to lung lymph flow.
The lymphatic vessels of the lung provide an important route for clearance of interstitial edema fluid filtered from pulmonary blood vessels. However, the importance of lung lymphatics for the removal of airway liquid filtered from the systemic circulation of the lung has not been demonstrated. We studied the contribution of the bronchial vasculature to lung lymph flow in anesthetized, ventilated sheep (n = 35). With the bronchial artery cannulated and perfused (control flow = 0.6 ml. min-1. kg-1), lymph flow from the efferent duct of the caudal mediastinal lymph node was measured 1) during increased bronchial vascular perfusion (300% of control flow); 2) with a hydrated interstitium induced by a 1-h period of left atrial hypertension and subsequent recovery, both with and without bronchial perfusion; and 3) during infusion (directly into the bronchial artery) of bradykinin, an inflammatory mediator known to cause changes in bronchial vascular permeability. Increased bronchial perfusion for 90 min resulted in an average 35% increase in lung lymph flow. During left atrial hypertension, the increase in lung lymph flow was significantly greater with bronchial perfusion (339% increase over baseline) than without bronchial perfusion (138% increase). Furthermore, recovery after left atrial hypertension was more complete after 90 min without bronchial perfusion (91%) than with bronchial perfusion (63%). Infusion of bradykinin into the bronchial artery resulted in a prompt and prolonged 107% increase in lung lymph flow. This was not seen if the same dose was infused into the pulmonary artery. Thus bronchial vascular transudate contributes significantly to lymph flow from the efferent duct of the caudal mediastinal lymph node. These results demonstrate that lymph vessels clear excess fluid from the airway wall and should be considered when evaluating the effect of vascular leak in airway obstruction.
Direct assessment of small airways reactivity in human subjects.
Our knowledge of airways reactivity to inflammatory agonists is derived predominantly from tests dominated by large airway responsiveness. To determine directly, the histamine responsiveness of the smallest airways, eight normal and 11 asymptomatic asthmatic subjects were studied utilizing a wedged bronchoscope technique. A fiberoptic bronchoscope was wedged in the anterior segment of the right upper lobe and a double-lumen catheter was advanced through the working channel to its tip. With a constant flow of gas (5% CO2 in air) through one lumen of the catheter, pressure at the tip of the bronchoscope was measured with the subject breath-holding at FRC. Peripheral airways resistance (Rp) was measured at baseline and after saline, histamine (10, 50, 100 mg/ml) and isoproterenol (2 mg/ml) challenge through the bronchoscope. Baseline Rp of asthmatics (0.041 +/- 0.015 cm H2O/ml/min; mean +/- SE) was significantly greater than normal subjects (0.011 +/- 0.003 cm H2O/ml/min; p = 0.019). The log of the concentration of histamine that caused a 100% increase in peripheral airways response was greater in the normal subjects than in the asthmatic subjects (p = 0.0114) and correlated with whole lung responsiveness to histamine in asthmatics (r = 0.847, p < 0.05). Isoproterenol reversed completely the increase in Rp in normal subjects but not asthmatic subjects. The results of this study demonstrate that the resistance of the smallest peripheral airways, when measured directly, increased when challenged locally with histamine in both normal subjects and asthmatic subjects. However, the peripheral airways responsiveness was significantly enhanced in asthmatic subjects relative to normal controls.
[The pre- and postoperative care of newborns with omphalocele or gastroschisis].
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[Care of children during high-frequency oscillation ventilation].
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[Temporary pacemaker therapy after heart surgery].
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Effect of lung inflation in vivo on airways with smooth muscle tone or edema.
Fibrous attachments to the airway wall and a subpleural surrounding pressure can create an external load against which airway smooth muscle must contract. A decrease in this load has been proposed as a possible cause of increased airway narrowing in asthmatic individuals. To study the interaction between the airways and the surrounding lung parenchyma, we investigated the effect of lung inflation on relaxed airways, airways contracted with methacholine, and airways made edematous by infusion of bradykinin into the bronchial artery. Measurements were made in anesthetized sheep by using high-resolution computed tomography to visualize changes in individual airways. During methacholine infusion, airway area was decreased but increased minimally with increases in transpulmonary pressure. Bradykinin infusion caused a 50% increase in airway wall area and an small decrease in airway luminal area. In contrast to airways contracted with methacholine, the luminal area after bradykinin increased substantially with increases in transpulmonary pressure, reaching 99% of the relaxed area at total lung capacity. Thus airway edema by itself did not prevent full distension of the airway at lung volumes approaching total lung capacity. Therefore, we speculate that if a deep inspiration fails to relieve airway narrowing in vivo, this must be a manifestation of airway smooth muscle contraction and not airway wall edema.
Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo.
Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83(2): 366-370, 1997.-Inflammatory changes and airway wall thickening are suggested to cause increased airway responsiveness in patients with asthma. In five sheep, the dose-response relationships of individual airways were measured at different lung volumes to methacholine (MCh) before and after wall thickening caused by the inflammatory mediator bradykinin via the bronchial artery. At 4 cmH2O transpulmonary pressure (Ptp), 5 microg/ml MCh constricted the airways to a maximum of 18 +/- 3%. At 30 cmH2O Ptp, MCh resulted in less constriction (to 31 +/- 5%). Bradykinin increased airway wall area at 4 and 30 cmH2O Ptp (159 +/- 6 and 152 +/- 4%, respectively; P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased airway luminal area (13 +/- 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH2O, postbradykinin, the maximal airway narrowing was not significantly different (26 +/- 5%; P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect on the MCh-induced airway constriction. We conclude that inflammatory fluid leakage in the airways cannot be a primary cause of airway hyperresponsiveness.
Effects of edema on small airway narrowing.
Numerous mediators of inflammation have been demonstrated to cause airway microvascular fluid and protein extravasation. That fluid extravasation results in airway wall edema leading to airway narrowing and enhanced reactivity has not been confirmed. In anesthetized, ventilated sheep (n = 30), airway vascular fluid extravasation was induced by infusing bradykinin (10(-6) M) through a cannulated, blood-perfused bronchial artery. Airway wall edema and luminal narrowing were determined morphometrically. Airway reactivity to methacholine (MCh; 10 microg/ml, intrabronchial artery) was determined by measuring conducting airway resistance (Raw) by forced oscillation. Raw measurements were made and lung lobes were excised and quick frozen before or after a 1-h bradykinin infusion. In 10 airways per lobe (range 0.2- to 2.0-mm relaxed diameter), wall area occupied 32 +/- 2% (SE) of the total normalized airway area (n = 9). Bradykinin infusion increased wall area to 42 +/- 5% (P = 0.02); luminal area decreased by <5%; and smooth muscle perimeter, a measure of smooth muscle constriction, was not altered (n = 5). Raw showed no change from baseline (1.4 +/- 0.4 cmH2O . l-1 . s) after bradykinin infusion (n = 10). During MCh challenge, Raw increased by 3.2 +/- 04 cmH2O . l-1 . s, and this change did not differ after administration of bradykinin. MCh challenge caused similar decreases in smooth muscle perimeter (10%) and luminal area (72 vs. 68%) before and after bradykinin infusion. However, the time constant of recovery of Raw from MCh constriction was increased from control (40 +/- 3 s) to 57 +/- 10 s after bradykinin infusion (P = 0.03). When lung lobes were excised at the same time after MCh challenge was terminated (n = 5), luminal area was greater before bradykinin infusion than after (86 vs. 78%; P = 0.007), as was smooth muscle perimeter. The results of this study demonstrate that airway wall edema limits relaxation after induced constriction rather than enhancing constriction.
[Reading and understanding reports on nursing research].
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Career development for women in academic medicine: Multiple interventions in a department of medicine.
OBJECTIVE: To determine the gender-based career obstacles for women in an academic department of medicine and to report the interventions to correct such obstacles (resulting from the evaluation) and the results of these interventions. DESIGN: Intervention study, before-after trial, with assessment of faculty concerns and perceived change through structured, self-administered questionnaires. SETTING: The Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md. PARTICIPANTS: Full-time faculty. INTERVENTIONS: Multifaceted intervention from 1990 through 1995 to correct gender-based career obstacles reported by women faculty, including problem identification, leadership, and education of faculty, and interventions to improve faculty development, mentoring, and rewards and to reduce isolation and structural career impediments. MAIN OUTCOME MEASURES: Retention and promotion of deserving women faculty, salary equity, quality of mentoring, decreased isolation from information and colleagues, integration of women faculty into the scientific community, and decreased manifestations of gender bias. RESULTS: Junior women were retained and promoted, reversing previous experience, with a 550% increase in the number of women at the associate professor rank over 5 years (from 4 in 1990 to 26 in 1995). Interim 3-year follow-up showed a 183% increase in the proportion of women faculty who expected they would still be in academic medicine in 10 years (from 23% [7/30] in 1990 to 65% [30/46] in 1993). One half to two thirds of women faculty reported improvements in timeliness of promotions, manifestations of gender bias, access to information needed for faculty development, isolation, and salary equity. Men also reported improvements in these areas. CONCLUSIONS: The outcomes reported here indicate that it is possible to make substantive improvements in the development of women's careers, that an institutional strategy to this end can be successful in retaining women in academic medicine, and that such interventions are likely to benefit all faculty. Long-term interventions appear essential.
Aerosol clearance by the bronchial circulation.
The importance of the tracheobronchial circulation in supporting mucociliary clearance is unclear. In anesthetized, ventilated sheep (n = 8), mucociliary transport of 99mTc-labeled sulfur colloid particles (2.1 microns) was measured during control perfusion of the cannulated bronchial branch of the bronchoesophageal artery or when perfusion through this artery was stopped. Particle retention 60 min after aerosol delivery of particles averaged 55% during control bronchial blood flow conditions. When perfusion was stopped, average retention was significantly increased to 76% (p < 0.05). These results indicate that the bronchial vasculature exerts an important modulating influence on mucociliary transport.
Effects of bronchial vascular engorgement on airway dimensions.
Airway vascular engorgement has been suggested to cause luminal narrowing and airflow obstruction. To determine the extent to which changes in bronchial vascular volume could influence airway dimensions, we studied the effects of left atrial pressure elevation on airway morphometry in sheep (n = 17). The bronchial branch of the bronchoesophageal artery was cannulated and perfused with autologous blood (0.6 ml.min-1.kg-1). A balloon-tipped catheter was inserted into the left atrial appendage to elevate left atrial pressure by 10 mmHg, and papaverine was infused into the bronchial artery to eliminate airway smooth muscle tone. Morphological measurements were made from rapidly frozen lungs excised in vivo. Left atrial pressure elevation caused a 79% increase in total vascular area (P = 0.0002). Average airway luminal area was significantly decreased from 86 to 71% of the airway maximal area (P < 0.0001). Noteworthy were the prominent bronchial vessels located within mucosal folds. However, when papaverine was infused during left atrial pressure elevation, despite a comparable total vascular area, luminal narrowing did not occur and remained at 87% of the maximal area (P = 0.6267). In conclusion, we found that engorgement of the bronchial vasculature leads to an increase in the vascular area in regions inside and outside the smooth muscle layer. The associated decrease in luminal area only occurs in the presence of airway smooth muscle tone. This suggests a reflex effect on the airway caused by the vascular engorgement. We conclude that vascular engorgement of the airway wall per se has a negligible effect on airway obstruction.