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Biomedical subjects

James A Frank

Publications and source records attributed to James A Frank.

9 recordsLinked to original sources
PubMed2006

Integrin alphavbeta5 regulates lung vascular permeability and pulmonary endothelial barrier function.

Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alphavbeta5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta [TGF-beta]). Knockout mice homozygous for a null mutation of the integrin beta5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of alphavbeta5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alphavbeta5, suggesting that alphavbeta5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alphavbeta5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.

Amides↗
PubMed2006

Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury.

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HV(T)) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HV(T) (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HV(T) (P < 0.05). BAL fluid from rats exposed to 20 min of HV(T) increased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

Animals↗
PubMed2006

Pathogenetic significance of biological markers of ventilator-associated lung injury in experimental and clinical studies.

For patients with acute lung injury, positive pressure mechanical ventilation is life saving. However, considerable experimental and clinical data have demonstrated that how clinicians set the tidal volume, positive end-expiratory pressure, and plateau airway pressure influences lung injury severity and patient outcomes including mortality. In order to better identify ventilator-associated lung injury (VALI), clinical investigators have sought to measure blood-borne and airspace biological markers of VALI. At the same time, several laboratory-based studies have focused on biological markers of inflammation and organ injury in experimental models in order to clarify the mechanisms of ventilator-induced lung injury (VILI) and VALI. This review summarizes data on biological markers of VALI and VILI from both clinical and experimental studies with an emphasis on markers identified in patients and in the experimental setting. This analysis suggests that measurement of some of these biological markers may be of value in diagnosing VALI and in understanding its pathogenesis.

Air Pressure↗
PubMed2005

Differential effects of sustained inflation recruitment maneuvers on alveolar epithelial and lung endothelial injury.

OBJECTIVE: The role of recruitment maneuvers in mechanical ventilation for patients with the acute respiratory distress syndrome and acute lung injury remains uncertain in part due to a lack of data on the effects of specific recruitment maneuvers on lung injury severity. The primary objective of this study was to determine the effect of one type of recruitment maneuver--sustained inflation--on alveolar epithelial and lung endothelial injury in experimental acute lung injury. DESIGN: Randomized experimental study. SETTING: Academic research laboratory. SUBJECTS: Forty-nine Sprague-Dawley rats. INTERVENTIONS: Lung injury was induced in anesthetized, ventilated rats by instillation of acid (pH 1.5) into the airspaces. Rats were ventilated with a tidal volume of 6 mL/kg and a positive end-expiratory pressure of 5 cm H(2)O with or without a sustained inflation recruitment maneuver repeated every 30 mins. Each recruitment maneuver consisted of two 30-sec inflations to total lung capacity (30 cm H(2)O) 1 min apart. MEASUREMENTS AND MAIN RESULTS: The use of recruitment maneuvers significantly improved oxygenation, compliance, end-expiratory lung volume, functional residual capacity, and deadspace fraction. Recruitment maneuvers reduced extravascular lung water and lung endothelial injury as measured by protein permeability (217 +/- 28 vs. 314 +/- 70 extravascular plasma equivalents [microL], p < .05). However, recruitment maneuvers did not prevent alveolar epithelial injury. Epithelial permeability and bronchoalveolar lavage RTI40 levels, a marker of type I cell injury, were similar with or without recruitment maneuvers. Recruitment maneuvers decreased epithelial fluid transport, a functional marker of epithelial injury. Recruitment maneuvers did not reduce markers of airspace inflammation. CONCLUSIONS: Sustained inflation recruitment maneuvers improve respiratory mechanics and oxygenation and may protect the lung endothelium but do not reduce alveolar epithelial injury. Because of the differential effects of recruitment maneuvers on the lung endothelium and alveolar epithelium, the net effect in clinical acute lung injury may not be beneficial. Additional clinical studies will be needed to assess the net impact of recruitment maneuvers in patients with acute lung injury.

Animals↗
PubMed2004

Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.

OBJECTIVE: To determine whether clinically relevant airspace concentrations of beta2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta2 agonist therapy decreased pulmonary edema in experimental acute lung injury. DESIGN: Prospective randomized laboratory investigation. SETTING: University-affiliated laboratory. SUBJECTS: Sprague Dawley rats. INTERVENTIONS: Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury. MEASUREMENTS AND MAIN RESULTS: Basal alveolar fluid clearance was 7.6 +/- 2.2 %/hr. Maximal cAMP-dependent alveolar fluid clearance rate was 32.9 +/- 10.9 %/hr (p <.05). Racemic albuterol 10(-5) M, salmeterol 10(-6) M, and isoproterenol 10(-6) M each stimulated alveolar fluid clearance to a level comparable to maximal cAMP-dependent alveolar fluid clearance. Compared with basal rates, alveolar fluid clearance was increased by both racemic albuterol 10(-6) M (14.5 +/- 3.0%, p <.05) and R-enantiomer 10(-6) M (15.0 +/- 4.6%, p <.05), but there was no difference between the two groups. Intra-alveolar salmeterol 10 (-6) M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 +/- 30 microL with salmeterol treatment, compared with 296 +/- 65 microL in saline-treated rats 4 hrs after acid injury (p <.05). This decrease in lung water was accompanied by a 2.4-fold increase in the rate of alveolar fluid clearance at 4 hrs in the salmeterol-treated group. Lung endothelial permeability, expressed as extravascular plasma equivalents, was reduced to 64 +/- 9 microL with salmeterol compared with 119 +/- 51 microL in saline-treated rats 4 hrs after acid injury (p <.05). CONCLUSIONS: Clinically relevant airspace concentrations of beta2-adrenergic agonists a) stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and b) reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability. Clinical studies are required to determine whether beta2-adrenergic agonists improve outcome in patients with acute lung injury.

Adenosine Monophosphate↗
PubMed2003

High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance.

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.

Acute Disease↗
PubMed2002

Science review: mechanisms of ventilator-induced injury.

Acute respiratory distress syndrome (ARDS) and acute lung injury are among the most frequent reasons for intensive care unit admission, accounting for approximately one-third of admissions. Mortality from ARDS has been estimated as high as 70% in some studies. Until recently, however, no targeted therapy had been found to improve patient outcome, including mortality. With the completion of the National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network low tidal volume study, clinicians now have convincing evidence that ventilation with tidal volumes lower than those conventionally used in this patient population reduces the relative risk of mortality by 21%. These data confirm the long-held suspicion that the role of mechanical ventilation for acute hypoxemic respiratory failure is more than supportive, in that mechanical ventilation can also actively contribute to lung injury. The mechanisms of the protective effects of low tidal volume ventilation in conjunction with positive end expiratory pressure are incompletely understood and are the focus of ongoing studies. The objective of the present article is to review the potential cellular mechanisms of lung injury attributable to mechanical ventilation in patients with ARDS and acute lung injury.

Cytokines↗
PubMed2002

Low tidal volume reduces epithelial and endothelial injury in acid-injured rat lungs.

Using a rat model of acid-induced lung injury, we tested the hypothesis that tidal volume reduction at the same level of PEEP (10 cm H(2)O) would diminish the degree of pulmonary edema by attenuating injury to the alveolar epithelial and endothelial barriers. Tidal volume reduction from 12 to 6 to 3 ml/kg significantly reduced the rate of lung water accumulation from 690 microl/h to 310 microl/h to 210 microl/h. Ventilation with either 6 or 3 ml/kg reduced endothelial injury equally as measured by plasma vWf:Ag and permeability to albumin. Plasma RTI40, a marker of type I epithelial cell injury, decreased 46% when tidal volume was reduced from 12 to 6 ml/kg and decreased an additional 33% with 3 ml/kg (p < 0.05). The rate of alveolar epithelial fluid clearance was significantly faster in the 3-ml/kg group (24 +/- 7%/h) compared with 6 ml/kg (15 +/- 11%/h) and 12 ml/kg (3 +/- 6%/h). We conclude that low tidal volume ventilation protects both the alveolar epithelium and the endothelium in this model of acute lung injury. The additional decrease in pulmonary edema with a tidal volume of 3 ml/kg is partly accounted for by greater protection of the alveolar epithelium.

Animals↗