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Biomedical subjects

M A Matthay

Publications and source records attributed to M A Matthay.

At least 91 records · Page 5Linked to original sources
PubMed1999

Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice.

The mammalian lung expresses water channel aquaporin-1 (AQP1) in microvascular endothelia and aquaporin-4 (AQP4) in airway epithelia. To test whether these water channels facilitate fluid movement between airspace, interstitial, and capillary compartments, we measured passive and active fluid transport in AQP1 and AQP4 knockout mice. Airspace-capillary osmotic water permeability (Pf) was measured in isolated perfused lungs by a pleural surface fluorescence method. Pf was remarkably reduced in AQP1 (-/-) mice (measured in cm/s x 0.001, SE, n = 5-10: 17 +/- 2 [+/+]; 6.6 +/- 0.6 AQP1 [+/-]; 1.7 +/- 0.3 AQP1 [-/-]; 12 +/- 1 AQP4 [-/-]). Microvascular endothelial water permeability, measured by a related pleural surface fluorescence method in which the airspace was filled with inert perfluorocarbon, was reduced more than 10-fold in AQP1 (-/-) vs. (+/+) mice. Hydrostatically induced lung interstitial and alveolar edema was measured by a gravimetric method and by direct measurement of extravascular lung water. Both approaches indicated a more than twofold reduction in lung water accumulation in AQP1 (-/-) vs. (+/+) mice in response to a 5- to 10-cm H2O increase in pulmonary artery pressure for five minutes. Active, near-isosmolar alveolar fluid absorption (Jv) was measured in in situ perfused lungs using 125I-albumin as an airspace fluid volume marker. Jv (measured in percent fluid uptake at 30 min, n = 5) in (+/+) mice was 6.0 +/- 0.6 (37 degrees C), increased to 16 +/- 1 by beta-agonists, and inhibited to less than 2.0 by amiloride, ouabain, or cooling to 23 degrees C. Jv (with isoproterenol) was not affected by aquaporin deletion (18.9 +/- 2.2 [+/+]; 16.4 +/- 1.5 AQP1 [-/-]; 16.3 +/- 1.7 AQP4 [-/-]). These results indicate that osmotically driven water transport across microvessels in adult lung occurs by a transcellular route through AQP1 water channels and that the microvascular endothelium is a significant barrier for airspace-capillary osmotic water transport. AQP1 facilitates hydrostatically driven lung edema but is not required for active near-isosmolar absorption of alveolar fluid.

Animals↗
PubMed1999

Acute pulmonary edema after lung transplantation: the pulmonary reimplantation response.

BACKGROUND: Although the development of noncardiogenic pulmonary edema or pulmonary reimplantation response (PRR) after lung transplantation has been well described, the incidence has not been established and the relationship of PRR to clinical risk factors has not been analyzed. STUDY OBJECTIVES: (1) To describe the incidence of PRR in lung transplant recipients, (2) to identify the predictors of PRR, (3) to examine the correlation of suspected predictors with the severity of PRR, and (4) to evaluate the impact of PRR on morbidity and mortality of lung transplant recipients. DESIGN: Retrospective review of clinical records and radiographic studies. SETTING: Tertiary care referral center. PATIENTS: Ninety-nine consecutive patients with end-stage lung disease undergoing lung transplantation between February 1990 and October 1995. METHODS: Review of clinical records and postoperative chest radiographs of all lung transplant recipients to identify patients who experienced PRR. Chest radiographs of patients with PRR were graded for severity on a scale of 0 (none) to 5 (very severe). Demographic, pre- and perioperative factors were also evaluated along with short- and long-term survival of patients with PRR. RESULTS: Fifty-six of 99 lung transplant recipients (57%) experienced PRR. The median ischemia time of patients with and without PRR was 168 and 180 min, respectively (p = 0.62). The incidence of PRR was 51% in patients without preoperative pulmonary hypertension, 78% in mild to moderate pulmonary hypertension, and 58% in patients with severe pulmonary hypertension (p = 0.10). Incidence and severity of PRR was similar in patients receiving right, left, or double-lung transplantation. Similarly, age and sex of the recipients and underlying lung disease did not affect the incidence or severity of PRR. The incidence and severity of PRR was higher in patients undergoing cardiopulmonary bypass during lung transplantation. Patients with PRR had prolonged duration of mechanical ventilation and ICU stay. Overall, PRR did not affect the survival of the patients. However, survival of female lung transplant recipients was significantly better than male recipients (median survival, 60 vs 21 months; p = 0.02). CONCLUSIONS: Acute pulmonary edema or PRR occurs frequently (57%) after lung transplantation. In this series, PRR was not associated with a prolonged ischemia time, preoperative pulmonary hypertension, the type of lung transplant, underlying lung disease, or age or sex of recipients. However, use of cardiopulmonary bypass during surgery was associated with increased incidence and severity of PRR. Also, the development of PRR resulted in prolonged mechanical ventilation and a longer ICU stay, but did not affect survival. Female lung transplant recipients survived significantly longer than male recipients. The reason for this difference in survival is unclear.

Acute Disease↗
PubMed1999

Interobserver variability in applying a radiographic definition for ARDS.

CONTEXT: Acute lung injury (ALI) and ARDS are currently defined by the American-European Consensus Conference (AECC) definition criteria, which contain a radiographic criterion. The accuracy or reliability of this consensus radiographic definition has not been evaluated, and no radiographic definition of ALI-ARDS has been evaluated by a large international group of experts. OBJECTIVE: To study the interobserver variability in applying the AECC radiographic criterion for ALI-ARDS. DESIGN: Survey. PARTICIPANTS: A convenience sample of 21 experts selected from participants attending the 1997 Toronto Mechanical Ventilation Workshop and from members of the National Institutes of Health ARDS Network. OUTCOME MEASURES: Participants reviewed 28 randomly selected chest radiograph from critically ill, hypoxemic (PaO(2)/fraction of inspired oxygen ratio, < 300) patients and decided whether the radiograph fulfilled the AECC definition for ALI-ARDS. RESULTS: Interobserver agreement in applying the AECC definition for ALI-ARDS was moderate (kappa = 0.55; 95% confidence interval, 0.52 to 0.57). Thirteen radiographs (43%) showed nearly complete agreement (defined as 20 or 21 readers in agreement). Nine radiographs (32%) had more than or equal to five dissenting readers. The percentage of radiographs interpreted as consistent with ALI-ARDS by individual readers ranged from 36 to 71%. Participants commented that mild infiltrates, pleural effusions, atelectasis, isolated lower lobe involvement, radiographic technique, and overlying monitoring equipment posed the most difficulties. CONCLUSIONS: The radiographic criterion used in the current AECC definition for ALI-ARDS showed high interobserver variability when applied by expert investigators in the fields of mechanical ventilation and ARDS. This variability may result in differences in ALI-ARDS populations at different clinical research centers and may make it difficult for clinicians to apply the results of clinical trials to their patients. Modifications to the radiographic criterion or annotated reference radiograph may improve the reliability of future definitions for ALI-ARDS.

Adolescent↗
PubMed1999

Exacerbation of acute pulmonary edema during assisted mechanical ventilation using a low-tidal volume, lung-protective ventilator strategy.

STUDY OBJECTIVES: To assess the magnitude of negative intrathoracic pressure development in a patient whose pulmonary edema acutely worsened immediately following the institution of a low-tidal volume (VT) strategy. DESIGN: Mechanical lung modeling of patient-ventilator interactions based on data from a case report. SETTING: Medical ICU and laboratory. PATIENT: A patient with suspected ARDS and frank pulmonary edema. INTERVENTIONS: The patient's pulmonary mechanics and spontaneous breathing pattern were measured. Samples of arterial blood and pulmonary edema fluid were obtained. MEASUREMENTS: A standard work-of-breathing lung model was used to mimic the ventilator settings, pulmonary mechanics, and spontaneous breathing pattern observed when pulmonary edema worsened. Comparison of the pulmonary edema fluid-to-plasma total protein concentration ratio was made. RESULTS: The patient's spontaneous VT demand was greater than preset. The lung model revealed simulated intrathoracic pressure changes consistent with levels believed necessary to produce pulmonary edema during obstructed breathing. A high degree of imposed circuit-resistive work was found. The pulmonary edema fluid-to-plasma total protein concentration ratio was 0.47, which suggested a hydrostatic mechanism. CONCLUSION: Ventilator adjustments that greatly increase negative intrathoracic pressure during the acute phase of ARDS may worsen pulmonary edema by increasing the transvascular pressure gradient. Therefore, whenever sedation cannot adequately suppress spontaneous breathing (and muscle relaxants are contraindicated), a low-VT strategy should be modified by using a pressure-regulated mode of ventilation, so that imposed circuit-resistive work does not contribute to the deterioration of the patient's hemodynamic and respiratory status.

Adult↗
PubMed1998

Highly water-permeable type I alveolar epithelial cells confer high water permeability between the airspace and vasculature in rat lung.

Water permeability measured between the airspace and vasculature in intact sheep and mouse lungs is high. More than 95% of the internal surface area of the lung is lined by alveolar epithelial type I cells. The purpose of this study was to test whether osmotic water permeability (Pf) in type I alveolar epithelial cells is high enough to account for the high Pf of the intact lung. Pf measured between the airspace and vasculature in the perfused fluid-filled rat lung by the pleural surface fluorescence method was high (0.019 +/- 0.004 cm/s at 12 degrees C) and weakly temperature-dependent (activation energy 3.7 kcal/mol). To resolve the contributions of type I and type II alveolar epithelial cells to lung water permeability, Pf was measured by stopped-flow light scattering in suspensions of purified type I or type II cells obtained by immunoaffinity procedures. In response to a sudden change in external solution osmolality from 300 to 600 mOsm, the volume of type I cells decreased rapidly with a half-time (t1/2) of 60-80 ms at 10 degrees C, giving a plasma membrane Pf of 0.06-0.08 cm/s. Pf in type I cells was independent of osmotic gradient size and was weakly temperature-dependent (activation energy 3.4 kcal/mol). In contrast, t1/2 for type II cells in suspension was much slower, approximately 1 s; Pf for type II cells was 0.013 cm/s. Vesicles derived from type I cells also had a very high Pf of 0.06-0.08 cm/s at 10 degrees C that was inhibited 95% by HgCl2. The Pf in type I cells is the highest measured for any mammalian cell membrane and would account for the high water permeability of the lung.

Animals↗
PubMed1998

The American-European Consensus Conference on ARDS, part 2. Ventilatory, pharmacologic, supportive therapy, study design strategies and issues related to recovery and remodeling.

The acute respiratory distress syndrome (ARDS) continues as a contributor to the morbidity and mortality of patients in intensive care units throughout the world, imparting tremendous human and financial costs. During the last ten years there has been a decline in ARDS mortality without a clear explanation. The American-European Consensus Committee on ARDS was formed to re-evaluate the standards for the ICU care of patients with acute lung injury (ALI), with regard to ventilatory strategies, the more promising pharmacologic agents, and the definition and quantification of pathological features of ALI that require resolution. It was felt that the definition of strategies for the clinical design and coordination of studies between centers and continents was becoming increasingly important to facilitate the study of various new therapies for ARDS.

Americas↗
PubMed1998

Risk reduction in the intensive care unit.

Many potentially preventable complications occur in patients who receive intensive care. We have reviewed the epidemiology of three important complications (venous thromboembolism, stress-related upper gastrointestinal bleeding, and vascular catheter-related infection) and evaluated common preventive treatments to provide evidence-based recommendations for prevention. We used English language articles located by MEDLINE or cross-citation, giving preference to articles published in the last 10 years, meta-analyses, and clinical trials that were randomized, double-blinded, and used intention-to-treat analysis. We recommend prophylaxis against venous thromboembolism in most patients, whereas those without respiratory failure or coagulopathy may not require prophylaxis against stress-related upper gastrointestinal hemorrhage. Chlorhexidine gluconate is the preferred antiseptic for disinfecting the skin prior to and during intravascular catheterization. Central venous catheters impregnated with antibacterial or antiseptic agents should be considered in patients at high risk for vascular catheter-related infection. Finally, central venous, pulmonary arterial, and systemic arterial catheters should be changed only when clinically indicated.

Arteries↗
PubMed1998

Pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerin tocolysis after open fetal surgery.

OBJECTIVES: This study was designed to determine the etiology, course, and severity of pulmonary edema in obstetric patients in a tertiary care center. STUDY DESIGN: A retrospective study was carried out on 16,810 deliveries from University of California, San Francisco, 1985-1995. Diagnosis and severity of lung injury were defined by a 4-point system that was based on the chest radiograph, oxygenation, positive end-expiratory pressure, and lung compliance. Resolution of pulmonary edema was defined by improvement in the chest radiograph and hypoxemia (ratio of arterial oxygen tension to inspired oxygen concentration) scores or by extubation. RESULTS: Pulmonary edema developed in 86 patients, or 0.5% of all obstetric cases. It usually showed extensive air space consolidation on the chest radiograph and arterial hypoxemia. Although 43% of the patients had severe pulmonary dysfunction, the average time to resolution of pulmonary edema was 2.4 days. Only 45% of patients required admission to the intensive care unit and only 15% required intubation and positive-pressure ventilation. Patients with infection (mean of 7.2 days) or fetal surgery (mean of 3.8 days) had the most severe, protracted course. CONCLUSION: Although obstetric pulmonary edema is associated with extensive radiographic infiltrates and severe hypoxemia, resolution occurs rapidly in most patients, limiting the need for intensive care support.

Critical Care↗
PubMed1998

High microvascular endothelial water permeability in mouse lung measured by a pleural surface fluorescence method.

Transport of water between the capillary and airspace compartments in lung encounters serial barriers: the alveolar epithelium, interstitium, and capillary endothelium. We previously reported a pleural surface fluorescence method to measure net capillary-to-airspace water transport. To measure the osmotic water permeability across the microvascular endothelial barrier in intact lung, the airspace was filled with a water-immiscible fluorocarbon. The capillaries were perfused via the pulmonary artery with solutions of specified osmolalites containing a high-molecular-weight fluorescent dextran. An increase in perfusate osmolality produced a prompt decrease in surface fluorescence due to dye dilution in the capillaries, followed by a slower return to initial fluorescence as capillary and lung interstitial osmolality equilibrate. A mathematical model was developed to determine the osmotic water permeability coefficient (Pf) of lung microvessels from the time course of pleural surface fluorescence. As predicted, the magnitude of the prompt change in surface fluorescence increased with decreased pulmonary artery perfusion rate and increased osmotic gradient size. With raffinose used to induce the osmotic gradient, Pf was 0.03 cm/s at 23 degrees C and was reduced 54% by 0.5 mM HgCl2. Temperature dependence measurements gave an Arrhenius activation energy (Ea) of 5.4 kcal/mol (12-37 degrees C). The apparent Pf induced by the smaller osmolytes mannitol and glycine was 0.021 and 0.011 cm/s (23 degrees C). Immunoblot analysis showed approximately 1.4 x 10(12) aquaporin-1 water channels/cm2 of capillary surface, which accounted quantitatively for the high Pf. These results establish a novel method for measuring osmotically driven water permeability across microvessels in intact lung. The high Pf, low Ea, and mercurial inhibition indicate the involvement of molecular water channels in water transport across the lung endothelium.

Animals↗
PubMed1998

A mouse model to test the in vivo efficacy of chemical chaperones.

In vitro studies in transfected cells have indicated that chemical chaperones including glycerol (0.5-1.2 M) and trimethylamine oxide (TMAO, 50-100 mM) can correct defective trafficking of some proteins, including deltaF508 CFTR in cystic fibrosis and AQP2 mutants in nephrogenic diabetes insipidus. To develop a mouse model to test the efficacy of chemical chaperones in vivo, glycerol and TMAO were administered by intraperitoneal (i.p.), subcutaneous (s.c.), and oral routes. Glycerol and TMAO assays that utilized 1-5 microL of tail vein blood were developed. Administration by the i.p. and s.c. routes gave maximum serum glycerol concentrations of approximately 100 mM, levels that were well below the effective in vitro concentrations. Single i.p. or s.c. doses of TMAO (7 g/kg, 8% solution in water) resulted in serum [TMAO] greater than 50 mM, with a long half-life (t1/2 approximately equal to 18-21 h). Sustained high serum and tissue [TMAO] > 52 mM for 3 days was achieved by s.c. administration of TMAO (7 g/kg) in water every 8 h. Although approximately 50% of the mice died with this multiple-dose regimen, the remaining mice had nearly normal liver, renal, and pancreatic function. A lower dose of TMAO (5 g/kg) given by the s.c. route every 8 h resulted in serum [TMAO] concentration of 22 mM, a level that was well tolerated by all mice for 72 h. These mice also had high [TMAO] in urine, 400 mM. These results demonstrate that potentially therapeutic concentrations of TMAO can be sustained in mice in vivo, permitting the testing of chemical chaperones in transgenic mouse models of diseases caused by defective protein trafficking.

Animals↗
PubMed1998

Effects of ATP-sensitive potassium channel opener on potassium transport and alveolar fluid clearance in the resected human lung.

Since the effect of an ATP-sensitive potassium channel (KATP channel) opener on the function of alveolar epithelial cells is unknown, the effect of YM934, a newly synthesized KATP channel opener, on potassium influx into the alveolar spaces and alveolar fluid clearance was determined in the resected human lung. An isosmolar albumin solution with a low potassium concentration was instilled into the distal airspaces of resected human lungs. Alveolar fluid clearance was measured by the progressive increase in alveolar protein concentration. Net potassium transport was measured by the change in potassium concentration and alveolar fluid volume. YM934 (10(-4) M) increased net influx of potassium by 140% into the alveolar spaces and also increased alveolar fluid clearance by 60% in the experiments with a potassium concentration of 0.3 mEq/1. Glibenclamide (10(-4) M), a KATP channel blocker, inhibited the YM934-increased influx of potassium transport and the increase in alveolar fluid clearance. Also amiloride (10(-5) M), an inhibitors of apical sodium uptake, blocked the YM934 stimulated increase in net alveolar fluid clearance. These results indicate that a KATP channel opener can effect potassium transport and net vectorial fluid movement across the human alveolar epithelium.

Adenosine Triphosphate↗
PubMed1998

Upregulation of alveolar epithelial fluid transport after subacute lung injury in rats from bleomycin.

Alveolar epithelial fluid transport was studied 10 days after subacute lung injury had been induced with intratracheal bleomycin (0.75 U). An isosmolar Ringer lactate solution with 5% bovine serum albumin and 125I-labeled albumin as the alveolar protein tracer was instilled into the right lung; the rats were then studied for either 1 or 4 h. Alveolar fluid clearance was increased in bleomycin-injured rats by 110% over 1 h and by 75% over 4 h compared with control rats (P < 0.05). The increase in alveolar fluid clearance was partially inhibited by amiloride (10(-3) M). Alveolar fluid clearance decreased toward normal levels in rats that were studied 60 days after bleomycin instillation. Remarkably, the measured increase in net alveolar fluid clearance occurred in the presence of a significant increase in alveolar epithelial permeability to protein. Moreover, the increase in alveolar epithelial fluid clearance occurred even though the mRNA for the alpha-subunit of the epithelial sodium channel was decreased in alveolar epithelial type II cells isolated from these rats. In addition, 22Na uptake by isolated alveolar epithelial type II cells from rats treated with bleomycin demonstrated a 52% decrease in uptake compared with type II cells from control rats. Morphological results demonstrated a significant hyperplasia of alveolar type II epithelial cells 10 days after bleomycin injury. Thus, these results provide evidence that proliferation of alveolar epithelial type II cells after acute lung injury may upregulate the transport capacity of the alveolar epithelium, even though the expression of epithelial sodium channels is reduced and the uptake of 22Na per cell is also reduced. These results may have clinical relevance for the resolution of alveolar edema in the subacute phase of lung injury.

Animals↗
PubMed1998

New in situ mouse model to quantify alveolar epithelial fluid clearance.

Because the availability of transgenic mice makes it possible to examine the contribution of single genes to in vivo function, we developed a simple in situ mouse model that can be used to quantify isosmolar alveolar epithelial fluid clearance (AFC). Mice were killed, a tracheostomy was done, and then a test solution of a 5% isosmolar albumin solution with 0.1 micro Ci of 125I-labeled albumin was instilled via the trachea into the distal air spaces of both lungs. After instillation, the lungs were inflated to 7 cmH2O with 100% O2 and maintained at 37 degrees C by placing the animals under an infrared lamp. AFC was measured by the progressive increase in concentration of labeled and unlabeled protein over 1 h. The results indicated the following. 1) Basal, unstimulated AFC in mouse lungs was significantly faster than in ex vivo rat lungs (27 +/- 5% in in situ mice vs. 11 +/- 3% in ex vivo rat lungs; P < 0.05). 2) Comparison of equivalent doses (10(-4) M) of beta-adrenergic agonist (isoproterenol) and beta2-adrenergic agonists (terbutaline and salmeterol) indicated that stimulated clearance occurred only in presence of isoproterenol. 3) Because atenolol, a specific beta1-antagonist, abolished the effect of isoproterenol, the beta-adrenergic stimulation appears to be mediated by beta1-receptors. The rate of AFC in nonperfused mouse lungs was significantly faster than in prior studies of nonperfused lungs in rats and sheep. Interestingly, the stimulated clearance rate in mice was similar to the fast rates of AFC that we recently reported in patients recovering from hydrostatic pulmonary edema. This in situ model is a unique experimental preparation that can be readily used to quantify isosmolar epithelial fluid clearance in mice.

Adrenergic beta-Agonists↗
PubMed1998

The American-European Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) continues as a contributor to the morbidity and mortality of patients in intensive care units throughout the world, imparting tremendous human and financial costs. During the last 10 years there has been a decline in ARDS mortality without a clear explanation. The American-European Consensus Committee on ARDS was formed to re-evaluate the standards for the ICU care of patients with acute lung injury (ALI), with regard to ventilatory strategies, the more promising pharmacologic agents, and the definition and quantification of pathologic features of ALI that require resolution. It was felt that the definition of strategies for the clinical design and coordination of studies between centers and continents was becoming increasingly important to facilitate the study of various new therapies for ARDS.

Europe↗