R W Glenny

University of Washington Seattle, Seattle, Washington, United States

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Publications (141)534.45 Total impact

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    ABSTRACT: Computational fluid dynamics (CFD) modeling is well-suited to addressing species-specific anatomy and physiology in calculating respiratory tissue exposures to inhaled materials. In this study, we overcame prior CFD model limitations to demonstrate the importance of realistic, transient breathing patterns for predicting site-specific tissue dose. Specifically, extended airway CFD models of the rat and human were coupled with airway region-specific physiologically based pharmacokinetic (PBPK) tissue models to describe the kinetics of three reactive constituents of cigarette smoke: acrolein, acetaldehyde and formaldehyde. Simulations of aldehyde no-observed-adverse-effect levels (NOAELs) for nasal toxicity in the rat were conducted until breath-by-breath tissue concentration profiles reached steady-state. Human oral breathing simulations were conducted using representative aldehyde yields from cigarette smoke, measured puff ventilation profiles and numbers of cigarettes smoked per day. As with prior steady-state CFD/PBPK simulations, the anterior respiratory nasal epithelial tissues received the greatest initial uptake rates for each aldehyde in the rat. However, integrated time- and tissue depth-dependent area under the curve (AUC) concentrations were typically greater in the anterior dorsal olfactory epithelium using the more realistic transient breathing profiles. For human simulations, oral and laryngeal tissues received the highest local tissue dose with greater penetration to pulmonary tissues than predicted in the rat. Based upon lifetime average daily dose (LADD) comparisons of tissue hot-spot AUCs (top 2.5% of surface area-normalized AUCs in each region) and numbers of cigarettes smoked/day, the order of concern for human exposures was acrolein > formaldehyde > acetaldehyde even though acetaldehyde yields were 10-fold greater than formaldehyde and acrolein.
    Toxicological Sciences 04/2015; DOI:10.1093/toxsci/kfv071 · 4.48 Impact Factor
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    ABSTRACT: -Despite its salutary effects on health, aerobic exercise is often avoided after receipt of an implantable cardioverter-defibrillator (ICD) because of fears that exercise may provoke acute arrhythmias. We prospectively evaluated the effects of a home aerobic exercise training and maintenance program (EX) on aerobic performance, ICD shocks and hospitalizations exclusively in ICD recipients. -One hundred sixty (124 men, 36 women) were randomized who had an ICD for primary (43%) or secondary (57%) prevention to EX or usual care (UC). The primary outcome was peak oxygen consumption (peakVO2), measured with cardiopulmonary exercise testing at baseline, 8 and 24 weeks. EX consisted of 8 weeks of home walking 1 hour/day, 5 days/week at 60-80% of heart rate reserve, followed by 16 weeks of maintenance home walking for 150 minutes/week. Adherence to EX was determined from exercise logs, ambulatory HR recordings of exercise, and weekly telephone contacts. UC received no exercise directives and were monitored by monthly telephone contact. Adverse events were identified by ICD interrogations, patient reports and medical records. ICD recipients averaged 55±12 years and mean ejection fraction of 40.6±15.7, all were taking beta blocker medications. EX significantly increased peakVO2 ml/kg/min (EX 26.7±7.0; UC 23.9±6.6, p=0.002) at 8 weeks, which persisted during maintenance exercise at 24 weeks (EX 26.9±7.7; UC 23.4±6.0, p<0.001). ICD shocks were infrequent (EX=4 vs UC=8), with no differences in hospitalizations or deaths between groups. -Prescribed home exercise is safe and significantly improves cardiovascular performance in ICD recipients without causing shocks or hospitalizations. -ClinicalTrials.gov. Identifier: NCT 00522340.
    Circulation 03/2015; 131(21). DOI:10.1161/CIRCULATIONAHA.114.014444 · 14.95 Impact Factor
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    ABSTRACT: ABSTRACT Purpose: Computer models for inhalation toxicology and drug-aerosol delivery studies rely on ventilation pattern inputs for predictions of particle deposition and vapor uptake. However, changes in lung mechanics due to disease can impact airflow dynamics and model results. It has been demonstrated that non-invasive, in vivo, 4DCT imaging (3D imaging at multiple time points in the breathing cycle) can be used to map heterogeneities in ventilation patterns under healthy and disease conditions. The purpose of this study was to validate ventilation patterns measured from CT imaging by exposing the same rats to an aerosol of fluorescent microspheres (FMS) and examining particle deposition patterns using cryomicrotome imaging. Materials and Methods: Six male Sprague-Dawley rats were intratracheally instilled with elastase to a single lobe to induce a heterogeneous disease. After four weeks, rats were imaged over the breathing cycle by CT then immediately exposed to an aerosol of ∼1μm FMS for ∼5 minutes. After the exposure, the lungs were excised and prepared for cryomicrotome imaging, where a 3D image of FMS deposition was acquired using serial sectioning. Cryomicrotome images were spatially registered to match the live CT images to facilitate direct quantitative comparisons of FMS signal intensity with the CT-based ventilation maps. Results: Comparisons of fractional ventilation in contiguous, non-overlapping, 3D regions between CT-based ventilation maps and FMS images showed strong correlations in fractional ventilation (r = 0.888, p < 0.0001). Conclusion: We conclude that ventilation maps derived from CT imaging are predictive of the 1μm aerosol deposition used in ventilation-perfusion heterogeneity inhalation studies.
    Experimental Lung Research 12/2014; 41(3). DOI:10.3109/01902148.2014.984085 · 1.75 Impact Factor
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    Dataset: JAP2004
  • Johan Petersson · Robb W Glenny
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    ABSTRACT: This review provides an overview of the relationship between ventilation/perfusion ratios and gas exchange in the lung, emphasising basic concepts and relating them to clinical scenarios. For each gas exchanging unit, the alveolar and effluent blood partial pressures of oxygen and carbon dioxide (PO2 and PCO2 ) are determined by the ratio of alveolar ventilation to blood flow (V'A/Q') for each unit. Shunt and low V'A/Q' regions are two examples of V'A/Q' mismatch and are the most frequent causes of hypoxaemia. Diffusion limitation, hypoventilation and low inspired PO2 cause hypoxaemia, even in the absence of V'A/Q' mismatch. In contrast to other causes, hypoxaemia due to shunt responds poorly to supplemental oxygen. Gas exchanging units with little or no blood flow (high V'A/Q' regions) result in alveolar dead space and increased wasted ventilation, i.e. less efficient carbon dioxide removal. Because of the respiratory drive to maintain a normal arterial PCO2 , the most frequent result of wasted ventilation is increased minute ventilation and work of breathing, not hypercapnia. Calculations of alveolar-arterial oxygen tension difference, venous admixture and wasted ventilation provide quantitative estimates of the effect of V'A/Q' mismatch on gas exchange. The types of V'A/Q' mismatch causing impaired gas exchange vary characteristically with different lung diseases.
    European Respiratory Journal 07/2014; 44(4). DOI:10.1183/09031936.00037014 · 7.13 Impact Factor
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    ABSTRACT: Ischemia-reperfusion lung injury is a common cause of acute morbidity and mortality in lung transplant recipients and has been associated with subsequent development of bronchiolitis obliterans syndrome. Recognition of endogenous ligands released during cellular injury (damage-associated molecular patterns; DAMPs) by Toll-like receptors (TLRs), especially TLR4, has increasingly been recognized as a mechanism for inflammation resulting from tissue damage. TLR4 is implicated in the pathogenesis of ischemia-reperfusion injury of multiple organs including heart, liver, kidney and lung. Additionally, activation of TLRs other than TLR4 by DAMPs has been identified in tissues other than the lung. Because all known TLRs, with the exception of TLR3, signal via the MyD88 adapter protein, we hypothesized that lung ischemia-reperfusion injury was mediated by MyD88-dependent signaling. To test this hypothesis, we subjected C57BL/6 wildtype, Myd88 (-/-) , and Tlr4 (-/-) mice to 1 hr of left lung warm ischemia followed by 4 hr of reperfusion. We found that Myd88 (-/-) mice had significantly less MCP-1/CCL2 in the left lung following ischemia-reperfusion as compared with wildtype mice. This difference was associated with dramatically reduced lung permeability. Interestingly, Tlr4 (-/-) mice had only partial protection from ischemia-reperfusion as compared to Myd88 (-/-) mice, implicating other MyD88-dependent pathways in lung injury following ischemia-reperfusion. We also found that left lung ischemia-reperfusion caused remote inflammation in the right lung. Finally, using chimeric mice with MyD88 expression restricted to either myeloid or non-myeloid cells, we found that MyD88-dependent signaling in myeloid cells was necessary for ischemia-reperfusion induced lung permeability. We conclude that MyD88-dependent signaling through multiple receptors is important in the pathogenesis of acute lung inflammation and injury following ischemia and reperfusion.
    PLoS ONE 10/2013; 8(10):e77123. DOI:10.1371/journal.pone.0077123 · 3.23 Impact Factor
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    ABSTRACT: A highly-automated method for the segmentation of airways in serial block-face cryomicrotome images of rat lungs is presented. First, a point inside of the trachea is manually specified. Then, a set of candidate airway centerline points is automatically identified. By utilizing a novel path extraction method, a centerline path between the root of the airway tree and each point in the set of candidate centerline points is obtained. Local disturbances are robustly handled by a novel path extraction approach, which avoids the shortcut problem of standard minimum cost path algorithms. The union of all centerline paths is utilized to generate an initial airway tree structure, and a pruning algorithm is applied to automatically remove erroneous subtrees or branches. Finally, a surface segmentation method is used to obtain the airway lumen. The method was validated on five image volumes of Sprague- Dawley rats. Based on an expert-generated independent standard, an assessment of airway identification and lumen segmentation performance was conducted. The average of airway detection sensitivity was 87.4% with a 95% confidence interval (CI) of (84.9, 88.6)%. A plot of sensitivity as a function of airway radius is provided. The combined estimate of airway detection specificity was 100% with a 95% CI of (99.4, 100)%. The average number and diameter of terminal airway branches was 1179 and 159 m, respectively. Segmentation results include airways up to 31 generations. The regression intercept and slope of airway radius measurements derived from final segmentations were estimated to be 7.22 m and 1.005, respectively. The developed approach enables quantitative studies of physiology and lung diseases in rats, requiring detailed geometric airway models.
    IEEE transactions on bio-medical engineering 08/2013; 61(1). DOI:10.1109/TBME.2013.2277936 · 2.23 Impact Factor
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    ABSTRACT: Prior studies exploring the spatial distributions of ventilation and perfusion have partitioned the lung into discrete regions not constrained by anatomical boundaries and may blur regional differences in perfusion and ventilation. To characterize the anatomical heterogeneity of regional ventilation and perfusion, we administered fluorescent microspheres to mark regional ventilation and perfusion in 5 Sprague-Dawley rats and then using highly automated computer algorithms, partitioned the lungs into regions defined by anatomical structures identified in the images. The anatomical regions ranged in size from the near-acinar to the lobar level. Ventilation and perfusion were well correlated at the smallest anatomical level. Perfusion and ventilation heterogeneity were relatively less in rats compared to data previously published in larger animals. The more uniform distributions may be due to a smaller gravitational gradient and/or the fewer number of generations in the distribution trees before reaching the level of gas exchange, making regional matching of ventilation and perfusion less extensive in small animals.
    Respiratory Physiology & Neurobiology 08/2013; 189(3). DOI:10.1016/j.resp.2013.07.027 · 1.97 Impact Factor
  • Melissa A Krueger · Sabine S Huke · Robb W Glenny
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    ABSTRACT: Rationale: The spatial distribution of blood flow in hearts of genetically modified mice is a phenotype of interest as derangements in blood flow may precede detectable changes in organ function. However, quantifying the regional distribution of blood flow within organs of mice is challenging because of the small organ volume and the high resolution required to observe spatial differences in flow. Traditional microsphere methods in which the numbers of microspheres per region are indirectly estimated from radioactive counts or extracted fluorescence have been limited to larger organs for two reasons; to assure statistical confidence in the measured flow per region and to be able to physically dissect the organ to acquire spatial information. Objective: We sought to develop methods to quantify and statistically compare the spatial distribution of blood flow within organs of mice. Methods and Results: We developed and validated statistical methods to compare blood flow between regions and to the same regions over time using 15 µm fluorescent microspheres. We then tested this approach by injecting fluorescent microspheres into isolated perfused mouse hearts, determining the spatial location of every microsphere in the hearts and then visualizing regional flow patterns. We demonstrated application of these statistical and visualizing methods in a coronary artery ligation model in mice. Conclusions: These new methods provide tools to investigate the spatial and temporal changes in blood flow within organs of mice at a much higher spatial resolution than currently available by other methods.
    Circulation Research 03/2013; 112(9). DOI:10.1161/CIRCRESAHA.113.301162 · 11.09 Impact Factor
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    ABSTRACT: In the current study, we used a canine model of radiation-induced lung injury to test the effect of a single i.v. infusion of 10×10(6)/kg of marrow fibroblasts on the progression of damage following 15 Gy exposure to the right lung. The fibroblasts, designated DS1 cells, are a cloned population of immortalized cells isolated from a primary culture of marrow stromal cells. DS1 cells were infused at week 5 post-irradiation when lung damage was evident by imaging with high-resolution computed tomography (CT). At 13 weeks post-irradiation we found that 4 out of 5 dogs receiving DS1 cells had significantly improved pulmonary function compared to 0 out of 5 control dogs (p = 0.047, Fisher's Exact). Pulmonary function was measured as the single breath diffusion capacity-hematocrit (DLCO-Hct), the total inspiratory capacity (IC), and the total lung capacity (TLC), which differed significantly between control and DS1-treated dogs; p = 0.002, p = 0.005, and p = 0.004, respectively. The DS1-treated dogs also had less pneumonitis detected by CT imaging and an increased number of TTF-1 (thyroid transcription factor 1, NKX2-1) positive cells in the bronchioli and alveoli compared to control dogs. Endothelial-like progenitor cells (ELC) of host origin, detected by colony assays, were found in peripheral blood after DS1 cell infusion. ELC numbers peaked one day after infusion, and were not detectable by 7 days. These data suggest that infusion of marrow fibroblasts stimulates mobilization of ELC, which is associated with a reduction in otherwise progressive radiation-induced lung injury. We hypothesize that these two observations are related, specifically that circulating ELC contribute to increased angiogenesis, which facilitates endogenous lung repair.
    PLoS ONE 03/2013; 8(3):e57179. DOI:10.1371/journal.pone.0057179 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND: Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary. METHODS: We validated PET-derived flow estimates with microsphere studies in 19 (9 rest, 10 stress) studies in five dogs. The radiotracer, (13)N-ammonia, was injected intravenously while microspheres were administered into the left atrium. A regional reduction in hyperemic flow was forced by an external occluder in five of the stress studies. The flow estimates from the axially distributed model were compared with estimates from conventional compartmental models. RESULTS: The mean difference between microspheres and the axially distributed blood flow estimates in each of the 17 segments was 0.03 mL/g/minute (95% CI [-0.05, 0.11]). The blood flow estimates were highly correlated with each regional microsphere value for the axially distributed model (y = 0.98x + 0.06 mL/g/minute; r = 0.74; P < .001), for the two-compartment (y = 0.64x + 0.34; r = 0.74; P < .001), and for three-compartment model (y = 0.69x + 0.54; r = 0.74; P < .001). The variance of the error of the estimates is higher with the axially distributed model than the compartmental models (1.7 [1.3, 2.1] times higher). CONCLUSION: The proposed axially distributed model provided accurate regional estimates of MBF. The axially distributed model estimated blood flow with more accuracy, but less precision, than the evaluated compartmental models.
    Journal of Nuclear Cardiology 10/2012; 20(1). DOI:10.1007/s12350-012-9632-8 · 2.65 Impact Factor
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    ABSTRACT: Performing exercise tests in patients with an implantable cardioverter defibrillator (ICD) presents specific challenges because of susceptibility to ventricular arrhythmias during maximal levels of exertion. The purpose of this paper is to outline the exercise testing protocol from the Anti-Arrhythmic Effects of Exercise after an ICD trial and to report baseline test results and safety outcomes using the protocol. Maximal cardiopulmonary exercise testing was performed to assess levels of physical fitness as part of a randomized trial of walking exercise in patients with ICDs. Subjects were randomized after baseline testing to aerobic exercise plus usual care or usual care alone. A modified Balke treadmill exercise test was used and specific ICD programming procedures were implemented to avoid unnecessary shocks, which included programming off ventricular tachycardia (VT) therapies during testing. To date, 161 baseline tests have been performed. One ventricular fibrillation (VF) cardiac arrest occurred following completion of an exercise test and three tests were stopped by the investigators due to nonsustained ventricular tachycardia. Eleven subjects were not able to achieve maximum exercise, defined as reaching an anaerobic threshold (AT) at baseline testing. There have been no deaths as a result of exercise testing. Symptom-limited maximal exercise testing can be performed safely and effectively in patients with ICDs for both primary and secondary prevention indications. Specific strategies for ICD programming and preparation for treating ventricular arrhythmias needs to be in place before exercise testing is performed.
    09/2012; 23(3):16-22.
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    ABSTRACT: We examine a previously published branch-based approach to modeling airway diameters that is predicated on the assumption of self-consistency across all levels of the tree. We mathematically formulate this assumption, propose a method to test it and develop a more general model to be used when the assumption is violated. We discuss the effect of measurement error on the estimated models and propose methods that account for it. The methods are illustrated on data from MRI and CT images of silicone casts of two rats, two normal monkeys and one ozone-exposed monkey. Our results showed substantial departures from self-consistency in all five subjects. When departures from selfconsistency exist we do not recommend using the self-consistency model, even as an approximation, as we have shown that it may likely lead to an incorrect representation of the diameter geometry. Measurement error has an important impact on the estimated morphometry models and needs to be accounted for in the analysis.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 06/2012; 295(6). DOI:10.1002/ar.22476 · 1.53 Impact Factor
  • Johan Petersson · Robb W Glenny
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    ABSTRACT: Several methods allow regional gas exchange to be inferred from imaging of regional ventilation and perfusion (V/Q) ratios. Each method measures slightly different aspects of gas exchange and has inherent advantages and drawbacks that are reviewed. Single photon emission computed tomography can provide regional measure of ventilation and perfusion from which regional V/Q ratios can be derived. PET methods using inhaled or intravenously administered nitrogen-13 provide imaging of both regional blood flow, shunt, and ventilation. Electric impedance tomography has recently been refined to allow simultaneous measurements of both regional ventilation and blood flow. MRI methods utilizing hyperpolarized helium-3 or xenon-129 are currently being refined and have been used to estimate local PaO(2) in both humans and animals. Microsphere methods are included in this review as they provide measurements of regional ventilation and perfusion in animals. One of their advantages is their greater spatial resolution than most imaging methods and the ability to use them as gold standards against which new imaging methods can be tested. In general, the reviewed methods differ in characteristics such as spatial resolution, possibility of repeated measurements, radiation exposure, availability, expensiveness, and their current stage of development.
    Journal of Applied Physiology 05/2012; 113(2):340-52. DOI:10.1152/japplphysiol.00173.2012 · 3.43 Impact Factor
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    ABSTRACT: Computational fluid dynamics (CFD) models are useful for predicting site-specific dosimetry of airborne materials in the respiratory tract and elucidating the importance of species differences in anatomy, physiology, and breathing patterns. We improved the imaging and model development methods to the point where CFD models for the rat, monkey, and human now encompass airways from the nose or mouth to the lung. A total of 1272, 2172, and 135 pulmonary airways representing 17±7, 19±9, or 9±2 airway generations were included in the rat, monkey and human models, respectively. A CFD/physiologically based pharmacokinetic model previously developed for acrolein was adapted for these anatomically correct extended airway models. Model parameters were obtained from the literature or measured directly. Airflow and acrolein uptake patterns were determined under steady-state inhalation conditions to provide direct comparisons with prior data and nasal-only simulations. Results confirmed that regional uptake was sensitive to airway geometry, airflow rates, acrolein concentrations, air:tissue partition coefficients, tissue thickness, and the maximum rate of metabolism. Nasal extraction efficiencies were predicted to be greatest in the rat, followed by the monkey, and then the human. For both nasal and oral breathing modes in humans, higher uptake rates were predicted for lower tracheobronchial tissues than either the rat or monkey. These extended airway models provide a unique foundation for comparing material transport and site-specific tissue uptake across a significantly greater range of conducting airways in the rat, monkey, and human than prior CFD models.
    Toxicological Sciences 05/2012; 128(2):500-16. DOI:10.1093/toxsci/kfs168 · 4.48 Impact Factor
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    ABSTRACT: To adapt an animal model of acute lung injury for use as a standard protocol for a screening initial evaluation of limited function, or "surge," ventilators for use in mass casualty scenarios. Prospective, experimental animal study. University research laboratory. Twelve adult pigs. Twelve spontaneously breathing pigs (six in each group) were subjected to acute lung injury/acute respiratory distress syndrome via pulmonary artery infusion of oleic acid. After development of respiratory failure, animals were mechanically ventilated with a limited-function ventilator (simplified automatic ventilator [SAVe] I or II; Automedx, Germantown, MD) for 1 hr or until the ventilator could not support the animal. The limited-function ventilator was then exchanged for a full-function ventilator (Servo 900C; Siemens-Elema, Solna, Sweden). Reliable and reproducible levels of acute lung injury/acute respiratory distress syndrome were induced. The SAVe I was unable to adequately oxygenate five animals with Pao2 (52.0±11.1 torr) compared to the Servo (106.0±25.6 torr; p=.002). The SAVe II was able to oxygenate and ventilate all six animals for 1 hr with no difference in Pao2 (141.8±169.3 torr) compared to the Servo (158.3±167.7 torr). We describe a novel in vivo model of acute lung injury/acute respiratory distress syndrome that can be used to initially screen limited-function ventilators considered for mass respiratory failure stockpiles and that is intended to be combined with additional studies to definitively assess appropriateness for mass respiratory failure. Specifically, during this study we demonstrate that the SAVe I ventilator is unable to provide sufficient gas exchange, whereas the SAVe II, with several more functions, was able to support the same level of hypoxemic respiratory failure secondary to acute lung injury/acute respiratory distress syndrome for 1 hr.
    Critical care medicine 03/2011; 39(3):527-32. DOI:10.1097/CCM.0b013e318206b99b · 6.15 Impact Factor
  • Robb W Glenny · H Thomas Robertson
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    ABSTRACT: With increasing spatial resolution of regional ventilation and perfusion, it has become more apparent that ventilation and blood flow are quite heterogeneous in the lung. A number of mechanisms contribute to this regional variability, including hydrostatic gradients, pleural pressure gradients, lung compressibility, and the geometry of the airway and vascular trees. Despite this marked heterogeneity in both ventilation and perfusion, efficient gas exchange is possible through the close regional matching of the two. Passive mechanisms, such as the shared effect of gravity and the matched branching of vascular and airway trees, create efficient gas exchange through the strong correlation between ventilation and perfusion. Active mechanisms that match local ventilation and perfusion play little if no role in the normal healthy lung but are important under pathologic conditions. © 2011 American Physiological Society. Compr Physiol 1:373-395, 2011.
    Comprehensive Physiology 01/2011; 1(1):375-95. DOI:10.1002/cphy.c100002 · 4.74 Impact Factor
  • Robb Glenny · H Thomas Robertson
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    ABSTRACT: Local driving pressures and resistances within the pulmonary vascular tree determine the distribution of perfusion in the lung. Unlike other organs, these local determinants are significantly influenced by regional hydrostatic and alveolar pressures. Those effects on blood flow distribution are further magnified by the large vertical height of the human lung and the relatively low intravascular pressures in the pulmonary circulation. While the distribution of perfusion is largely due to passive determinants such as vascular geometry and hydrostatic pressures, active mechanisms such as vasoconstriction induced by local hypoxia can also redistribute blood flow. This chapter reviews the determinants of regional lung perfusion with a focus on vascular tree geometry, vertical gradients induced by gravity, the interactions between vascular and surrounding alveolar pressures, and hypoxic pulmonary vasoconstriction. While each of these determinants of perfusion distribution can be examined in isolation, the distribution of blood flow is dynamically determined and each component interacts with the others so that a change in one region of the lung influences the distribution of blood flow in other lung regions. © 2011 American Physiological Society. Compr Physiol 1:245-262, 2011.
    Comprehensive Physiology 01/2011; 1(1):245-62. DOI:10.1002/cphy.c100012 · 4.74 Impact Factor
  • Robb W Glenny · H Thomas Robertson
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    ABSTRACT: The primary function of the pulmonary circulation is to deliver blood to the alveolar capillaries to exchange gases. Distributing blood over a vast surface area facilitates gas exchange, yet the pulmonary vascular tree must be constrained to fit within the thoracic cavity. In addition, pressures must remain low within the circulatory system to protect the thin alveolar capillary membranes that allow efficient gas exchange. The pulmonary circulation is engineered for these unique requirements and in turn these special attributes affect the spatial distribution of blood flow. As the largest organ in the body, the physical characteristics of the lung vary regionally, influencing the spatial distribution on large-, moderate-, and small-scale levels. © 2011 American Physiological Society. Compr Physiol 1:39-59, 2011.
    Comprehensive Physiology 01/2011; 1(1):39-59. DOI:10.1002/cphy.c090002 · 4.74 Impact Factor
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    ABSTRACT: Real-time imaging of cellular and subcellular dynamics in vascularized organs requires image resolution and image registration to be simultaneously optimized without perturbing normal physiology. This problem is particularly pronounced in the lung, in which cells may transit at speeds >1 mm s(-1) and in which normal respiration results in large-scale tissue movements that prevent image registration. Here we report video-rate, two-photon imaging of a physiologically intact preparation of the mouse lung that is stabilizing and nondisruptive. Using our method, we obtained evidence for differential trapping of T cells and neutrophils in mouse pulmonary capillaries, and observed neutrophil mobilization and dynamic vascular leak in response to stretch and inflammatory models of lung injury in mice. The system permits physiological measurement of motility rates of >1 mm s(-1), observation of detailed cellular morphology and could be applied in the future to other organs and tissues while maintaining intact physiology.
    Nature Methods 01/2011; 8(1):91-6. DOI:10.1038/nmeth.1543 · 25.95 Impact Factor

Publication Stats

3k Citations
534.45 Total Impact Points


  • 1990–2015
    • University of Washington Seattle
      • • Department of Medicine
      • • Division of Pulmonary and Critical Care Medicine
      Seattle, Washington, United States
  • 2004–2009
    • Karolinska University Hospital
      • Department of Pediatric Anesthesiology and Intensive Care
      Tukholma, Stockholm, Sweden
  • 1994–2005
    • Indiana University-Purdue University Indianapolis
      • • Department of Cellular and Integrative Physiology
      • • Department of Anesthesia
      Indianapolis, Indiana, United States
  • 2002
    • University of Texas Southwestern Medical Center
      • Department of Internal Medicine
      Dallas, TX, United States
  • 1999
    • Kansas State University
      • Department of Anatomy and Physiology
      Manhattan, KS, United States
  • 1996
    • Spokane VA Medical Center
      Spokane, Washington, United States