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Results for “PULMONARY LUNG MODEL”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Tiny Device Mimics Human Lung Function

Scientists at Los Alamos National Laboratory are developing a miniature, tissue-engineered artificial lung that mimics the response of the human lung to drugs, toxins and other agents. “We breathe in and out thousands of times every day. And while we have control over what we eat or drink, we don’t always have control over what we breathe in,” said Jennifer Harris of Biosecurity and Public Health at Los Alamos, "and so we’re making this miniature lung to be able to test on actual human cells whether something in the environment, or a drug, is toxic or harmful to us." Nicknamed “PuLMo” for Pulmonary Lung Model (Pulmo is also the Latin word for "lung")the device consists of two major parts, the bronchiolar unit and the alveolar unit—just like the human lung. The units are primarily made from various polymers and are connected by a microfluidic “circuit board” that manages fluid and air flow. “When we build our lung, we not only take into account the aspects of different cell types, the tissues that are involved, we also take into account that a lung is supposed to breathe, so PuLMo actually breathes,” said Pulak Nath of Applied Modern Physics, who leads engineering efforts for the project. The most exciting application of PuLMo is a potentially revolutionary improvement in the reliability of drug-toxicity assessments and the prediction of new pharmaceutical success in humans, according to Harris. The PuLMo may also be designed to mimic lung disease conditions, such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, and may be used to study lung air-flow dynamics to better understand the mechanisms of toxins and drug delivery and the effects of smoking, particularly the less-understood effects of e-cigarettes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Pulmo (V.2.0): Miniaturized Artificial, Configurable Human Lung System of Systems for Accelerated Toxicological Studies

The Pulmonary Lung Model (PuLMo) Version 2.0 is a miniaturized, engineered human artificial lung organ, designed to mimic the responses of human lungs to pharmaceuticals, toxins, and other agents. It can be customized in a system of systems implementation to reduce the life-cycle time and cost of pulmonary toxicological studies.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2025

Vitamin E Acetate Causes Softening of Pulmonary Surfactant Membrane Models

The popularity of electronic cigarettes and vaping products has launched the outbreak of a condition affecting the respiratory system of users, known as electronic-cigarette/vaping-associated lung injury (EVALI). The build-up of vitamin E acetate (VEA), a diluent of some illicit vaping oils, in the bronchoalveolar lavage of patients with EVALI provided circumstantial evidence as a target for investigation. In this work, we provide a fundamental characterization of the interaction of VEA with lung cells and pulmonary surfactant (PS) models to explore the mechanisms by which vaping-related lung injuries may be present. We first confirm the localization and uptake of VEA in pulmonary epithelial cells. Further, as PS is vitally responsible for the biophysical functions of the lungs, we explore the effect of added VEA on three increasingly complex models of PS: dipalmitoylphosphatidylcholine (DPPC), a lipid-only synthetic PS, and the biologically derived extract Curosurf. Using high-resolution techniques of small-angle X-ray scattering, small-angle neutron scattering, neutron spin–echo spectroscopy, and neutron reflectometry, we compare the molecular-scale behaviors of these membranes to the bulk viscoelastic properties of surfactant monolayer films as studied by Langmuir monolayer techniques. While VEA does not obviously alter the structure or organization of PS membranes, a consistent softening of membrane systems—regardless of compositional complexity—provides a biophysical explanation for the respiratory distress associated with EVALI and yields a new perspective on the behavior of the PS system.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Computer-aided pulmonary image analysis in small animal models

Purpose: To develop an automated pulmonary image analysis framework for infectious lung diseases in small animal models. Methods: The authors describe a novel pathological lung and airway segmentation method for small animals. The proposed framework includes identification of abnormal imaging patterns pertaining to infectious lung diseases. First, the authors’ system estimates an expected lung volume by utilizing a regression function between total lung capacity and approximated rib cage volume. A significant difference between the expected lung volume and the initial lung segmentation indicates the presence of severe pathology, and invokes a machine learning based abnormal imaging pattern detection system next. The final stage of the proposed framework is the automatic extraction of airway tree for which new affinity relationships within the fuzzy connectedness image segmentation framework are proposed by combining Hessian and gray-scale morphological reconstruction filters. Results: 133 CT scans were collected from four different studies encompassing a wide spectrum of pulmonary abnormalities pertaining to two commonly used small animal models (ferret and rabbit). Sensitivity and specificity were greater than 90% for pathological lung segmentation (average dice similarity coefficient > 0.9). While qualitative visual assessments of airway tree extraction were performed by the participating expert radiologists, for quantitative evaluation the authors validated the proposed airway extraction method by using publicly available EXACT’09 data set. Conclusions: The authors developed a comprehensive computer-aided pulmonary image analysis framework for preclinical research applications. The proposed framework consists of automatic pathological lung segmentation and accurate airway tree extraction. The framework has high sensitivity and specificity; therefore, it can contribute advances in preclinical research in pulmonary diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Stable Small Animal Mechanical Ventilation for Dynamic Lung Imaging to Support Computational Fluid Dynamics Models

Pulmonary computational fluid dynamics models require 3D images to be acquired over multiple points in the dynamic breathing cycle, with no breath holds or changes in ventilatory mechanics. With small animals, these requirements result in long imaging times ({approx}90 minutes), over which lung mechanics, such as compliance, can gradually change if not carefully monitored and controlled. These changes, caused by derecruitment of parenchymal tissue, are manifested as an upward drift in peak inspiratory pressure or by changes in the pressure waveform and/or lung volume over the course of the experiment. We demonstrate highly repeatable mechanical ventilation in anesthetized rats over a long duration for pulmonary CT imaging throughout the dynamic breathing cycle. We describe significant updates to a basic commercial ventilator that was acquired for these experiments. Key to achieving consistent results was the implementation of periodic deep breaths, or sighs, of extended duration to maintain lung recruitment. In addition, continuous monitoring of breath-to-breath pressure and volume waveforms and long-term trends in peak inspiratory pressure and flow provide diagnostics of changes in breathing mechanics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Mice overexpressing latent matrix metalloproteinase-2 develop lung emphysema after short-term exposure to cigarette smoke extract

Highlights: • Protease/anti-protease imbalance is an important event in the pathogenesis of lung emphysema. • Long time exposure to cigarette smoke is generally required to induce mouse model of lung emphysema. • Mice overexpressing matrix metalloproteinase-2 develop lung emphysema after short exposure to cigarette smoke extract. Chronic obstructive pulmonary disease is the major growing cause of mortality and morbidity worldwide, and it is going to become the third most common cause of death by 2020. Chronic obstructive pulmonary disease is pathologically characterized by lung emphysema and small airway inflammation. Animal models are very important to get insights into the disease pathogenesis but current models of chronic obstructive pulmonary disease take a long time to develop. The need of a new model is compelling. In the present study we focus on the role of matrix metalloproteinases in the pathogenesis of chronic obstructive pulmonary disease and hypothesized that lung overexpression of latent matrix metalloproteinases-2 would allow the development of emphysema after short-term exposure to cigarette smoke extract inhalation. Human latent matrix metalloproteinases-2 transgenic mouse expressing high level of the protein in the lungs and wild type mouse were exposed to aerosolized cigarette smoke extract for two weeks. Transgenic mice showed significant lung emphysematous changes, increased infiltration of inflammatory cells and enhanced lung concentrations of inflammatory cytokines in the lungs compared to their wild type counterparts after inhalation of cigarette smoke extract. This novel mouse model will be a very useful tool for evaluating the mechanistic pathways and for development of novel therapies in cigarette smoke-associated lung emphysema.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

A bidirectional coupling procedure applied to multiscale respiratory modeling

In this study, we present a novel multiscale computational framework for efficiently linking multiple lower-dimensional models describing the distal lung mechanics to imaging-based 3D computational fluid dynamics (CFDs) models of the upper pulmonary airways in order to incorporate physiologically appropriate outlet boundary conditions. The framework is an extension of the modified Newton’s method with nonlinear Krylov accelerator developed by Carlson and Miller [1], Miller [2] and Scott and Fenves [3]. Our extensions include the retention of subspace information over multiple timesteps, and a special correction at the end of a timestep that allows for corrections to be accepted with verified low residual with as little as a single residual evaluation per timestep on average. In the case of a single residual evaluation per timestep, the method has zero additional computational cost compared to uncoupled or unidirectionally coupled simulations. We expect these enhancements to be generally applicable to other multiscale coupling applications where timestepping occurs. In addition we have developed a “pressure-drop” residual which allows for stable coupling of flows between a 3D incompressible CFD application and another (lower-dimensional) fluid system. We expect this residual to also be useful for coupling non-respiratory incompressible fluid applications, such as multiscale simulations involving blood flow. The lower-dimensional models that are considered in this study are sets of simple ordinary differential equations (ODEs) representing the compliant mechanics of symmetric human pulmonary airway trees. To validate the method, we compare the predictions of hybrid CFD–ODE models against an ODE-only model of pulmonary airflow in an idealized geometry. Subsequently, we couple multiple sets of ODEs describing the distal lung to an imaging-based human lung geometry. Boundary conditions in these models consist of atmospheric pressure at the mouth and intrapleural pressure applied to the multiple sets of ODEs. In both the simplified geometry and in the imaging-based geometry, the performance of the method was comparable to that of monolithic schemes, in most cases requiring only a single CFD evaluation per time step. Thus, this new accelerator allows us to begin combining pulmonary CFD models with lower-dimensional models of pulmonary mechanics with little computational overhead. Moreover, because the CFD and lower-dimensional models are totally separate, this framework affords great flexibility in terms of the type and breadth of the adopted lower-dimensional model, allowing the biomedical researcher to appropriately focus on model design. Research funded by the National Heart and Blood Institute Award 1RO1HL073598.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Single-energy computed tomography-based pulmonary perfusion imaging: Proof-of-principle in a canine model

Purpose: Radiotherapy (RT) that selectively avoids irradiating highly functional lung regions may reduce pulmonary toxicity, which is substantial in lung cancer RT. Single-energy computed tomography (CT) pulmonary perfusion imaging has several advantages (e.g., higher resolution) over other modalities and has great potential for widespread clinical implementation, particularly in RT. The purpose of this study was to establish proof-of-principle for single-energy CT perfusion imaging. Methods: Single-energy CT perfusion imaging is based on the following: (1) acquisition of end-inspiratory breath-hold CT scans before and after intravenous injection of iodinated contrast agents, (2) deformable image registration (DIR) for spatial mapping of those two CT image data sets, and (3) subtraction of the precontrast image data set from the postcontrast image data set, yielding a map of regional Hounsfield unit (HU) enhancement, a surrogate for regional perfusion. In a protocol approved by the institutional animal care and use committee, the authors acquired CT scans in the prone position for a total of 14 anesthetized canines (seven canines with normal lungs and seven canines with diseased lungs). The elastix algorithm was used for DIR. The accuracy of DIR was evaluated based on the target registration error (TRE) of 50 anatomic pulmonary landmarks per subject for 10 randomly selected subjects as well as on singularities (i.e., regions where the displacement vector field is not bijective). Prior to perfusion computation, HUs of the precontrast end-inspiratory image were corrected for variation in the lung inflation level between the precontrast and postcontrast end-inspiratory CT scans, using a model built from two additional precontrast CT scans at end-expiration and midinspiration. The authors also assessed spatial heterogeneity and gravitationally directed gradients of regional perfusion for normal lung subjects and diseased lung subjects using a two-sample two-tailed t-test. Results: The mean TRE (and standard deviation) was 0.6 ± 0.7 mm (smaller than the voxel dimension) for DIR between pre contrast and postcontrast end-inspiratory CT image data sets. No singularities were observed in the displacement vector fields. The mean HU enhancement (and standard deviation) was 37.3 ± 10.5 HU for normal lung subjects and 30.7 ± 13.5 HU for diseased lung subjects. Spatial heterogeneity of regional perfusion was found to be higher for diseased lung subjects than for normal lung subjects, i.e., a mean coefficient of variation of 2.06 vs 1.59 (p = 0.07). The average gravitationally directed gradient was strong and significant (R{sup 2} = 0.99, p < 0.01) for normal lung dogs, whereas it was moderate and nonsignificant (R{sup 2} = 0.61, p = 0.12) for diseased lung dogs. Conclusions: This canine study demonstrated the accuracy of DIR with subvoxel TREs on average, higher spatial heterogeneity of regional perfusion for diseased lung subjects than for normal lung subjects, and a strong gravitationally directed gradient for normal lung subjects, providing proof-of-principle for single-energy CT pulmonary perfusion imaging. Further studies such as comparison with other perfusion imaging modalities will be necessary to validate the physiological significance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. • Acute effects of chlorine were pulmonary edema, hypoxemia and impaired lung function. • Persistent small airway disease developed following recovery from acute injury. • Small airway disease included inflammation and bronchiolitis obliterans lesions. • The model should be useful for studying chlorine lung injury and testing treatments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-β1 induction in a rat model of chlorine-induced lung injury

We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl{sub 2}) with the aim to understand the pathogenesis of the long-term sequelae of Cl{sub 2}-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time-course from 5 h up to 90 days after a single inhalation of Cl{sub 2}. A single dose of dexamethasone (10 mg/kg) was administered 1 h following Cl{sub 2}-exposure. A 15-min inhalation of 200 ppm Cl{sub 2} was non-lethal in Sprague-Dawley rats. At 24 h post exposure, Cl{sub 2}-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart. At 24 h, the inflammasome-associated cytokines IL-1β and IL-18 were detected in BAL. Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-β expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24 h but did not influence the AHR. Inhalation of Cl{sub 2} in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-β1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl{sub 2}-induced respiratory dysfunction. - Highlights: • Inhalation of Cl{sub 2} leads to acute lung inflammation and airway hyperreactivity. • Cl{sub 2} activates an inflammasome pathway of TGF-β induction. • Cl{sub 2} leads to a fibrotic respiratory disease. • Treatment with corticosteroids alone is insufficient to counteract acute lung injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Pulmonary lobe segmentation based on ridge surface sampling and shape model fitting

Purpose: Performing lobe-based quantitative analysis of the lung in computed tomography (CT) scans can assist in efforts to better characterize complex diseases such as chronic obstructive pulmonary disease (COPD). While airways and vessels can help to indicate the location of lobe boundaries, segmentations of these structures are not always available, so methods to define the lobes in the absence of these structures are desirable. Methods: The authors present a fully automatic lung lobe segmentation algorithm that is effective in volumetric inspiratory and expiratory computed tomography (CT) datasets. The authors rely on ridge surface image features indicating fissure locations and a novel approach to modeling shape variation in the surfaces defining the lobe boundaries. The authors employ a particle system that efficiently samples ridge surfaces in the image domain and provides a set of candidate fissure locations based on the Hessian matrix. Following this, lobe boundary shape models generated from principal component analysis (PCA) are fit to the particles data to discriminate between fissure and nonfissure candidates. The resulting set of particle points are used to fit thin plate spline (TPS) interpolating surfaces to form the final boundaries between the lung lobes. Results: The authors tested algorithm performance on 50 inspiratory and 50 expiratory CT scans taken from the COPDGene study. Results indicate that the authors' algorithm performs comparably to pulmonologist-generated lung lobe segmentations and can produce good results in cases with accessory fissures, incomplete fissures, advanced emphysema, and low dose acquisition protocols. Dice scores indicate that only 29 out of 500 (5.85%) lobes showed Dice scores lower than 0.9. Two different approaches for evaluating lobe boundary surface discrepancies were applied and indicate that algorithm boundary identification is most accurate in the vicinity of fissures detectable on CT. Conclusions: The proposed algorithm is effective for lung lobe segmentation in absence of auxiliary structures such as vessels and airways. The most challenging cases are those with mostly incomplete, absent, or near-absent fissures and in cases with poorly revealed fissures due to high image noise. However, the authors observe good performance even in the majority of these cases.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Exosomes derived from endothelial progenitor cells ameliorate acute lung injury by transferring miR-126

Highlights: • Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo lung integrity. • The microRNA miR-126 was enriched in EPC-Exos and the abilities of EPC-Exos to protect against LPS were relayed by the horizontal shuttled miR-126. • Transferred miR-126 to target endothelial cells downregulated SPRED1 and implicated RAF/ERK signaling pathways in the reparative process in rat model of lung injury. Endothelial progenitor cell (EPC) has potential to attenuate pulmonary inflammation and injury. As a pivotal paracrine entity of stem cells, whether EPC-derived exosomes (EPC-Exos) contribute to acute lung injury (ALI) remains unknown. Exosomes were purified from conditional medium of EPCs, and then characterized by electron micrograph and immunoblotting. A model of ALI was induced by lipopolysaccharide (LPS) and then rats were transplanted with EPC-Exos. The underlying mechanisms of action of EPC-Exos were examined in vitro endothelial functional assays including the TEER, proliferation (CKK-8), angiogenesis and migration. A possible underlying mechanism was examined by western blotting and further animal studies. Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo pulmonary integrity. EPC-Exos enhanced the proliferation, migration and tube formation of the endothelial cells (ECs). Furthermore, we found that miR-126 was enriched in EPC-Exos and can be delivered onto ECs. Modification of EPCs through miR-126 knockdown can diminish their exosomes function in vitro, indicative of the abilities of EPC-Exos to protect against LPS were inherited by the horizontal shuttled miR-126. Luciferase reporter assays confirmed that miR-126 could target SPRED1. Additionally, the miR-126 transferred to target endothelial cells resulted in subsequent downregulation of SPRED1 and promoted RAF/ERK signaling pathways and subsequent improvement in endothelial cell function. Our study revealed a novel role of exosomal miRNAs in EPC-mediated therapy, suggesting that the clinical application of EPC-Exos might represent a strategy in ALI/ARDS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular hypertrophy and restored airway responsiveness.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE 2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE 2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

Ozone (O{sub 3})-related cardiorespiratory effects are a growing public health concern. Ground level O{sub 3} can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O{sub 3}-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O{sub 3} pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O{sub 3} exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O{sub 2}) or hypoxia (10.0% O{sub 2}), followed by a 4-h exposure to either 1 ppm O{sub 3} or filtered air (FA). As an additional experimental intervention fasudil (20 mg/kg) was administered intraperitoneally prior to and after O{sub 3} exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O{sub 3} exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O{sub 3} exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O{sub 3}-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. - Highlights: • Environmental exposures can exacerbate chronic obstructive pulmonary disease (COPD). • It is unknown if comorbid pulmonary hypertension may influence such effects in COPD patients. • Pulmonary hypertension in a mouse model significantly exacerbated ozone-induced lung injury. • Adverse ozone outcomes were largely attenuated by a rho kinase inhibitor, fasudil. • Therapeutic benefit from rho kinase inhibition may be related to endothelial barrier integrity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Quantification of regional early stage gas exchange changes using hyperpolarized {sup 129}Xe MRI in a rat model of radiation-induced lung injury

Purpose: To assess the feasibility of hyperpolarized (HP) {sup 129}Xe MRI for detection of early stage radiation-induced lung injury (RILI) in a rat model involving unilateral irradiation by assessing differences in gas exchange dynamics between irradiated and unirradiated lungs. Methods: The dynamics of gas exchange between alveolar air space and pulmonary tissue (PT), PT and red blood cells (RBCs) was measured using single-shot spiral iterative decomposition of water and fat with echo asymmetry and least-squares estimation images of the right and left lungs of two age-matched cohorts of Sprague Dawley rats. The first cohort (n = 5) received 18 Gy irradiation to the right lung using a {sup 60}Co source and the second cohort (n = 5) was not irradiated and served as the healthy control. Both groups were imaged two weeks following irradiation when radiation pneumonitis (RP) was expected to be present. The gas exchange data were fit to a theoretical gas exchange model to extract measurements of pulmonary tissue thickness (L{sub PT}) and relative blood volume (V{sub RBC}) from each of the right and left lungs of both cohorts. Following imaging, lung specimens were retrieved and percent tissue area (PTA) was assessed histologically to confirm RP and correlate with MRI measurements. Results: Statistically significant differences in L{sub PT} and V{sub RBC} were observed between the irradiated and non-irradiated cohorts. In particular, L{sub PT} of the right and left lungs was increased approximately 8.2% and 5.0% respectively in the irradiated cohort. Additionally, V{sub RBC} of the right and left lungs was decreased approximately 36.1% and 11.7% respectively for the irradiated cohort compared to the non-irradiated cohort. PTA measurements in both right and left lungs were increased in the irradiated group compared to the non-irradiated cohort for both the left (P < 0.05) and right lungs (P < 0.01) confirming the presence of RP. PTA measurements also correlated with the MRI measurements for both the non-irradiated (r = 0.79, P < 0.01) and irradiated groups (r = 0.91, P < 0.01). Conclusions: Regional RILI can be detected two weeks post-irradiation using HP {sup 129}Xe MRI and analysis of gas exchange curves. This approach correlates well with histology and can potentially be used clinically to assess radiation pneumonitis associated with early RILI to improve radiation therapy outcomes.

60 APPLIED LIFE SCIENCES↗