In vivo function of an interleukin 2 receptor beta chain (IL-2Rbeta)/IL-4Ralpha cytokine receptor chimera potentiates allergic airway disease.

Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor beta chain [IL-2Rbeta] extracellular domain fused to the cytoplasmic tail of IL-4Ralpha) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4-specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell-specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).

Right ventricular hypertrophy is an important determinant of right ventricular infarction complicating acute inferior left ventricular infarction.

To explore the role of right ventricular hypertrophy and chronic obstructive pulmonary disease in the pathogenesis of right ventricular infarction, 27 consecutive patients with a first inferior left ventricular infarction were prospectively studied. Right ventricular infarction was diagnosed using established hemodynamic criteria. Right ventricular hypertrophy was defined as right ventricular free wall thickness greater than or equal to 5 mm. Patients were classified into two groups: Group I patients with right ventricular infarction (n = 15), and Group II patients without right ventricular infarction (n = 12). The ratio of forced expiratory volume over forced vital capacity (FEV1/FVC) and forced expiratory flow between 25 and 75% expired volume (FEF) as a percent of predicted values were significantly reduced in Group I versus Group II (90 +/- 5 versus 105 +/- 6% and 63 +/- 13 versus 103 +/- 15%, respectively; p less than 0.05). This was associated with increased right ventricular wall thickness (Group I 5.5 +/- 0.3 mm versus Group II 3.9 +/- 0.2 mm, p less than 0.001). Multiple logistic regression analysis demonstrated that right ventricular wall thickness was the strongest predictor of right ventricular infarction (p less than 0.0005). No significant difference was found in the site of right coronary occlusion, collateral blood supply or extent of coronary artery disease between the two groups. These findings suggest that right ventricular hypertrophy predisposes patients with acute inferior myocardial infarction to right ventricular infarction independent of the site or extent of coronary artery disease.

Ethnic differences in response to morphine.

Only recently has attention been focused on the importance of interethnic differences as determinants of interindividual variability in drug response. We compared the pharmacokinetics and pharmacodynamics of morphine in eight Chinese and eight white healthy mean after 0.15 mg/kg of morphine intravenously. The clearance of morphine was significantly higher in the Chinese subjects than in the white subjects because of an increase in the partial metabolic clearance by glucuronidation. There was no interethnic difference in the metabolism to normorphine. Morphine depressed the respiratory response to rebreathing carbon dioxide more in white subjects than in Chinese subjects, resulting in a greater reduction in resting ventilation and resting end-tidal PCO2. The slope of the ventilation/PCO2 response curve, a measure of carbon dioxide sensitivity, was reduced more in white subjects than Chinese subjects. As a result, white subjects had a greater depression in ventilation at a PCO2 of 55 mm Hg. The morphine-induced reduction in blood pressure was also greater in white subjects than in Chinese subjects. Thus this study has shown ethnicity to be an important determinant of the disposition and effects of morphine.

IL-4 signaling, gene transcription regulation, and the control of effector T cells.

The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.

Use of pulse oximetry to recognize severity of airflow obstruction in obstructive airway disease: correlation with pulsus paradoxus.

STUDY OBJECTIVES: The purpose of this cross-sectional study was to confirm the observation that pulse oximetry tracing correlates with pulsus paradoxus, and is therefore a measure of the severity of air trapping in obstructive airway disease. DESIGN: Cross-sectional survey. SETTING: The ICU in a tertiary care academic hospital. PATIENTS: Twenty-six patients consecutively admitted to the ICU with obstructive airway disease, either asthma or COPD. MEASUREMENTS AND RESULTS: Forty-six percent of the study patients required mechanical ventilation, and 69% had an elevated pulsus paradoxus. We defined the altered pulse oximetry baseline tracing as the respiratory waveform variation (RWV). The RWV was measured in numerical form as the change in millimeters from the baseline. Pulsus paradoxus was significantly correlated with the RWV of the pulse oximetry tracing (p < 0.0001). An analysis of the respiratory variations in the pulse oximetry waveforms in obstructive lung disease patients reflects the presence and degree of auto-positive end-expiratory pressure (auto-PEEP; p < 0.0001). CONCLUSIONS: We describe the characteristic alterations in the pulse oximetry tracings that occur in the presence of pulsus paradoxus and auto-PEEP. Since pulse oximetry is available universally in ICUs and emergency departments, it may be a useful noninvasive means of continually assessing pulsus paradoxus and air trapping severity in obstructive airway disease patients.

Pulmonary function in long-term survivors of hyaline membrane disease.

In order to determine the long-term pulmonary consequences of hyaline membrane disease (HMD), we measured pulmonary function and airway responsiveness to methacholine in 22 survivors of HMD aged 18 to 22 years. Nineteen age-matched control subjects without a history of lung disease or asthma were also studied. There was no statistically significant difference between the mean pulmonary function test results of the control vs the HMD group. The mean N2 delta of the five HMD patients who required assisted ventilation was significantly different from that of the control group. Airway responsiveness to methacholine, as estimated by the dose of methacholine aerosol necessary to provoke a 35 percent fall in SGaw did not differ between the control and HMD groups. In the absence of prematurity, low birth weight (less than 1,500 g), and requirement for positive pressure ventilation, HMD is not associated with an increase in nonspecific airway reactivity or abnormal pulmonary function in adulthood.

EP(2) receptor mediates bronchodilation by PGE(2) in mice.

PGE(2) is an important cyclooxygenase product that modulates airway inflammatory and smooth muscle responses. Signal transduction is mediated by four EP receptor subtypes that cause distinct effects on cell metabolism. To determine the role of EP(2) receptor activation, we produced a mouse lacking the EP(2) receptor by targeted gene disruption. The effect of aerosolized PGE(2) and other agonists was measured using barometric plethysmography and by measurements of lung resistance in mechanically ventilated mice. Inhalation of PGE(2) inhibited methacholine responses in wild-type but not in mice lacking the EP(2) receptor [EP(2)(-/-)]. After airway constriction was induced by methacholine aerosol, PGE(2) reduced the airway constriction enhanced pause in wild-type mice (from 0.88 +/- 0.15 to 0.55 +/- 0.06) but increased it in EP(2)(-/-) mice (from 0.73 +/- 0. 08 to 1.27 +/- 0.19). Similar results were obtained in mechanically ventilated mice. These data indicate that the EP(2) receptor mediates the bronchodilation effect of PGE(2).

Acute effects of thoracic irradiation on lung function and structure in awake sheep.

To investigate the acute physiological and structural changes after lung irradiation, the effects of whole-lung irradiation were investigated in fourteen sheep. Ten sheep were prepared with vascular and chronic lung lymph catheters, then a week later were given 1,500 rad whole-lung radiation and monitored for 2 days. Four sheep were given the same dose of radiation and were killed 4 h later for structural studies. Lung lymph flow increased at 3 h after radiation (14.6 +/- 2.1 ml/h) to twice the base-line flow rate (7.5 +/- 1.3), with a high lymph-to-plasma protein concentration. Pulmonary arterial pressure increased twofold from base line (18 +/- 1.6 cmH2O) at 2 h after radiation (33 +/- 3.8). Cardiac output and systemic pressure in the aorta did not change after lung radiation. Arterial O2 tension decreased from 85 +/- 3 to 59 +/- 4 Torr at 1 day after radiation. Lymphocyte counts in both blood and lung lymph decreased to a nadir by 4 h and remained low. Thromboxane B2 concentration in lung lymph increased from base line (0.07 +/- 0.03 ng/ml) to peak at 3 h after radiation (8.2 +/- 3.7 ng/ml). The structural studies showed numerous damaged lymphocytes in the peripheral lung and bronchial associated lymphoid tissue. Quantitative analysis of the number of granulocytes in peripheral lung showed no significant change (base line 6.2 +/- 0.8 granulocytes/100 alveoli, 4 h = 10.3 +/- 2.3). The most striking change involved lung airways. The epithelial lining of the majority of airways from intrapulmonary bronchus to respiratory bronchiolus revealed damage with the appearance of intracellular and intercellular cell fragments and granules. This new large animal model of acute radiation lung injury can be used to monitor physiological, biochemical, and morphological changes after lung radiation. It is relevant to the investigation of diffuse oxidant lung injury as well as to radiobiology per se.

Prematurity is associated with abnormal airway function in childhood.

To evaluate the long-term effect of prematurity and/or hyaline membrane disease (HMD) on pulmonary function and airway reactivity, we studied 49 prematurely born children aged 10 to 13 years. They were divided into three groups according to birth weight and HMD status: Groups I and II comprised the children weighing less than 1,500 g at birth, and Group III those whose birth weight exceeded 1,500 g. Children without HMD at birth were classified as Group I and those with HMD as Group II or III. We performed both pulmonary function tests and methacholine (MCh) challenges and compared the results with those of 27 age-matched controls born at term. We found that FEV1 and RV/TLC ratios were significantly different from control values in the groups with birth weights less than 1,500 g, regardless of their HMD status (Groups I and II). In Group I, results for FEF25-75%, Vmax50%, and DLCO were lower than those of controls. Airway reactivity was significantly increased in Groups I and II. A 20% drop in FEV1 after MCh challenge was found in 88%, 62%, 53%, and 36% of children in Groups I, II, and III and controls, respectively, and a 35% drop in SGaw occurred in 87%, 88%, 53%, and 59%. We conclude that prematurity and not HMD per se leads to long-term pulmonary abnormalities and to an increase in nonspecific airway reactivity.

CNS tuberculosis.

Tuberculous meningitis is a rare, treatable neurologic disorder, in which early recognition is paramount because outcome depends greatly on the speed with which therapy is initiated. Patients with meningitis and CSF findings of low glucose, elevated protein and pleocytosis with evidence of tuberculosis elsewhere in the body (chest radiographs, positive tuberculin skin test), or a history of exposure to tuberculosis should be treated immediately with antituberculous medication. When the diagnosis remains uncertain, serial examination of the CSF for tuberculous organisms will often yield positive results. The CT scan may show hydrocephalus, a basilar arachnoiditis, or intraparenchymal lesions: tuberculomas. Hydrocephalus may respond to early shunting. Tuberculomas are best treated medically. Therapy should include INH and rifampin; ethambutol and pyrazinamide are suggested for the first 2 months of therapy. Steroids may be useful in diminishing the inflammatory response when altered consciousness or focal neurologic signs are present.

Quantitative analysis of cyclooxygenase metabolites of arachidonic Acid.

Metabolism of arachidonic acid results in a host of biologically active compounds with profound effects on airway inflammation (1). After activation of cellular phospholipases and release of free arachidonic acid, catalyzed insertion of oxygen occurs enzymatically via action of one of the two known cyclooxygenase isoenzymes (COX-1 and COX-2). The unstable bicyclic intermediate, PGH(2), undergoes subsequent metabolism to form prostaglandins (PG), thromboxane (Tx), and leukotrienes (LT) (see Fig.1). In addition, free radicals can oxygenate arachidonate although it is bound to the diacylgycerol backbone of membrane phospholipids. The family of compounds formed in this way, known as isoprostanes, are stereochemically different and incorporate a large number of regioisomeric compounds that may confound measurement of PG (2-5 and see Chapter 33 ). Arachidonic acid can also be metabolized by specific cytochrome P(450) enzymes to regioisomeric epoxides and stereo specific hydro xyeicosatetraenoic (HETE) acids (6). Fig. 1. Overview of pathways of metabolism of arachidonic acid during airway inflammation. Following activation of cellular phospholipases, arachidonic acid is cleaved from membrane phospholipids. It is undergoing dioxygenation catalyzed by cyclooxygenase (either COX-1 or COX-2 isoforms) to form the unstable endoperoxide intermediate PGH2. Specific isomerases with varied cellular distribution further metabolize PGH2 to bioactive prostaglandins and thromboxanes.

Quantitative analysis of f(2) isoprostanes.

The discoveries by Jack Roberts and Jason Morrow of the nonenzymatic oxidation of cell membrane phospholipids to form isoprostanes has revolutionized the field of eicosanoids (1). Prior to their discoveries, it was dogma that the important biologically active eicosanoids were formed by enzymes acting on arachidonic acid that had been cleaved from phospholipids by the action of phospholipases. Their research has clearly shown that important biologically active fatty acid metabolites are formed in a variety of inflammatory conditions from the action of oxygen radicals on arachidonic acid, while it is still present in complex phospholipids. These oxidized compounds may alter cell structure and signaling, and when released by the action of phospholipases, are immediately available to bind to receptors to modulate cell activity. The free radical attack on arachidonate yields an endoperoxide which can then be transformed nonenzymatically to F, D, E ring prostaglandins. Thus, each enzymatically formed eicosanoid appears to have its own class of isoprostanes, including isothromboxanes (2,3). Likewise, the isoleukotrienes have been described. In addition, compounds such as the hydroxyeicosatetraenoic acids (HETEs) can also be formed in this fashion (4,5). The biologic activity of these compounds is only now being examined.

Asthma: emerging concepts and potential therapies.

Asthma is a disease of the airways that results in reversible airflow obstruction. Recent investigations have suggested that airway inflammation is associated with increased airway responsiveness and worsening of asthmatic symptoms. The role that mast cell mediators might play in the production of asthma has been investigated by use of newer analytical techniques and by use of fiberoptic bronchoscopy with lavage to obtain lower respiratory tract fluid and cells. In addition, new investigational compounds that interfere with the synthesis or action of inflammatory mediators have been tested. Developing lines of investigation suggest that chronic activation of inflammatory cells may be important in the pathogenesis of asthma.

Postpneumonic empyema in childhood: selecting appropriate therapy.

In order to identify appropriate treatment options for postpneumonic empyema, we reviewed the medical records and, when possible, obtained long-term follow-up chest radiographs and pulmonary function tests on children treated for empyema during the past 11 years. Fifty-one patients were treated in various ways, with antibiotics alone (N = 10), or in combination with tube thoracostomy (N = 23) or decortication (N = 18). Despite administration of appropriate antibiotics and establishment of pleural drainage, many children required prolonged hospitalization and eventual decortication. Based on this review, a scoring system was developed allowing early classification by severity of pleural disease. Factors found to be predictors of severe pleural disease include (1) low pleural fluid pH or (2) glucose; (3) presence of moderate or severe scoliosis or (4) pleural peel or parenchymal entrapment by chest radiography; and (5) infection due to anaerobes, gram-negative organisms, or mycoplasma. Complete opacification of a hemithorax on chest radiography and a pleural peel to thoracic ratio greater than 40% were also associated with severe pleural disease. In patients with mild disease (N = 7), response to antibiotics alone, rapid resolution of fever, and shorter hospital stays were observed. In patients with more severe infections (moderate = 22, severe = 22), decortication accomplished earlier defervescence, radiographic improvement, and hospital discharge than simple tube thoracostomy. No deaths or morbidity were associated with decortication, which could often be accomplished through a minithoracotomy. Follow-up chest radiographs and pulmonary fuction tests showed a prompt return to normal after decortication. This experience indicates utility of a pleural disease severity scoring system in selection of treatment options for children with postpneumonic empyema.(ABSTRACT TRUNCATED AT 250 WORDS)

Flow volume loops in the evaluation of upper airway obstruction.

Patients with lesions that cause obstruction of the large airways are often misdiagnosed as having chronic lung disease or reactive airways disease. Close attention to the history and physical examination provides clues to the presence of a laryngeal or tracheal lesion. Obtaining a flow volume loop in the pulmonary function laboratory is a simple and effective method of noninvasively evaluating a patient for the presence of an upper airway obstruction. Fixed lesions cause plateaus in both the inspiratory and expiratory limbs of the flow volume loop. Variable intrathoracic lesions are characterized by expiratory slowing and flattening of the expiratory limb. An important caveat is that these changes may not be present in a patient with coexisting lower airway disease such as COPD or asthma. Variable extrathoracic lesions cause inspiratory slowing and a plateau on the inspiratory limb of the flow volume loop. Finally, the clinician should remember that the quality of the flow volume loop is totally dependent on the patient's effort and cooperation and, thus, that the tracings obtained in the pulmonary function laboratory may not have the classic shapes presented in this review.

Childhood pulmonary function following hyaline membrane disease.

Hyaline membrane disease per se is not associated with abnormal lung function or increased nonspecific airway reactivity in childhood or adulthood. Very-low-birth-weight infants who survive almost routinely in neonatal ICUs are at risk, however, for developing airflow obstruction and having airway hyperreactivity as children, and for having recurrent bouts of wheezing, cough, and respiratory infections. Neonates who develop BPD have the greatest risk of abnormal pulmonary function as children. Continued research into the prevention of premature birth and into the causes of neonatal lung injury, combined with improvements in the neonatal ICU and follow-up treatment, will undoubtedly contribute to improvement in the clinical course of premature infants.

New therapies for asthma.

Asthma is an inflammatory disease. Therefore, effective doses of antiinflammatory agents, particularly inhaled steroids, should have prominent place in the hierarchy of treatment, even in mild asthma. Suppression of airway inflammation may result in reduction of the need for bronchodilators, and perhaps the morbidity and mortality of asthma.

Inhaled steroids in asthma.

Inhaled steroids are the mainstay of anti-inflammatory treatment of asthma. Topical application of steroids to the asthmatic airway has many benefits as well as potential side effects; however, the side effects are much less prevalent than those caused by the use of chronic oral prednisone.

Viral infections in asthma.

This article summarizes recent findings regarding the impact of viruses on reactive airway disease. Technical breakthroughs are improving our ability to diagnosis viral infections. However, the real breakthrough will come when pharmacologic interventions can specifically prevent the symptoms of virally induced asthma.