American Thoracic Society Documents an Official Ats Conference Proceedings: Advances in Small-animal Imaging Application to Lung Pathophysiology Executive Summary Background Methods Small-animal Models of Lung Disease Asthma Models Copd Interstitial Lung Disease Acute Lung Injury Imaging Modalities

The American Thoracic Society convened a workshop, ‘‘Advances in Small Animal Imaging: Application to Lung Pathophysiology,’’ to identify cutting-edge research in imaging technology and the potential applicability to the study of lung pathophysiology in small-animal models. The goals of the conference were as follows: (1) to summarize the current state of small-animal models of lung pathophysiology and their applicability to human disease; (2) to identify all potential modes of noninvasive imaging; (3) to explore the potential for current and future applications; (4) to discuss and debate current controversies; and (5) to identify future research directions and opportunities for, and applications of, imaging technology to facilitate the use of small-animal models for the study of lung diseases. The first part of the workshop focused on the current state of knowledge of mouse models with an emphasis on ‘‘What are the big questions?’’ and ‘‘How good are the models?’’ Presentations described four major animal model systems of lung disease: (1) reactive airway disease, (2) chronic obstructive pulmonary disease (COPD) and emphysema, (3) interstitial lung disease, and (4) acute lung injury (ALI). The second part of the workshop reviewed those ‘‘state of the art’’ imaging modalities that would be most likely applicable to lung disease with an emphasis on the questions ‘‘What is the cutting edge of the imaging modality?’’ and ‘‘What can we measure with this imaging modality?’’ The related presentations focused on six imaging modalities that have received the most recent attention: (1) videomicroscopy, (2) magnetic resonance imaging (MRI), (3) micro-computed tomography (micro-CT), (4) micro-positron emission tomography (micro-PET), (5) optical imaging, and (6) molecular markers. The final part of the workshop was devoted to discussion and interaction between those investigators focused on development of imaging modalities and those using small-animal models of lung disease. The discussion included (1) the quality and applicability of current small-animal models of lung disease and (2) how to better adapt currently available imaging modalities to study lung disease in small-animal models. Workshop participants concluded that noninvasive imaging of health and disease in living organisms can span several domains, including anatomic, physiologic, metabolic, and molecular imaging. In parallel, technologies have evolved that allow us to query biological processes at multiple levels, including X-ray/CT, MRI, nuclear imaging (single photon emission CT [SPECT]/PET), ultrasound, and optical imaging (bioluminescence/fluorescence). ‘‘Molecular imaging’’ refers to the measurement and characterization of specific molecules, molecular processes, and molecular events, over time and space, in living organisms. Furthermore, whereas imaging modalities may be applicable to small animals, the currently used small-animal models of common human lung diseases remain limited in terms of their ability to truly recapitulate human pathophysiologic conditions. Further development is required for small-animal models of human lung disease as well as the integrated use of imaging modalities. The following recommendations were made for future work on animal models:

[1]  EN Li-ping,et al.  Proceedings of the American Thoracic Society , 2008 .

[2]  J. Bates,et al.  The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[3]  S. Shapiro,et al.  Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease , 2006, European Respiratory Journal.

[4]  S. Shapiro,et al.  Animal models of asthma: Pro: Allergic avoidance of animal (model[s]) is not an option. , 2006, American journal of respiratory and critical care medicine.

[5]  S. Holgate,et al.  The mouse trap: It still yields few answers in asthma. , 2006, American journal of respiratory and critical care medicine.

[6]  G Allan Johnson,et al.  Imaging alveolar–capillary gas transfer using hyperpolarized 129Xe MRI , 2006, Proceedings of the National Academy of Sciences.

[7]  Sanjiv S Gambhir,et al.  Bifunctional antibody-Renilla luciferase fusion protein for in vivo optical detection of tumors. , 2006, Protein engineering, design & selection : PEDS.

[8]  W. Weber Positron emission tomography as an imaging biomarker. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  R. Pauwels,et al.  Murine models of COPD. , 2006, Pulmonary pharmacology & therapeutics.

[10]  Michael E Phelps,et al.  Impact of animal handling on the results of 18F-FDG PET studies in mice. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[11]  R. Weissleder Molecular Imaging in Cancer , 2006, Science.

[12]  Thomas Guerrero,et al.  Novel method to calculate pulmonary compliance images in rodents from computed tomography acquired at constant pressures , 2006, Physics in medicine and biology.

[13]  Clemens van Blitterswijk,et al.  Bioluminescent imaging: emerging technology for non-invasive imaging of bone tissue engineering. , 2006, Biomaterials.

[14]  L. Hedlund,et al.  A liposomal nanoscale contrast agent for preclinical CT in mice. , 2006, AJR. American journal of roentgenology.

[15]  Patrick L Chow,et al.  A method of image registration for small animal, multi-modality imaging , 2006, Physics in medicine and biology.

[16]  Jiangsheng Yu,et al.  Measurements of regional alveolar oxygen pressure using hyperpolarized 3He MRI. , 2005, Academic radiology.

[17]  Anna M Wu,et al.  Arming antibodies: prospects and challenges for immunoconjugates , 2005, Nature Biotechnology.

[18]  R. Homer,et al.  Back to the future: historical perspective on the pathogenesis of idiopathic pulmonary fibrosis. , 2005, American journal of respiratory cell and molecular biology.

[19]  David Piwnica-Worms,et al.  Real-time imaging of ligand-induced IKK activation in intact cells and in living mice , 2005, Nature Methods.

[20]  Z. Zhou,et al.  Physiologic, biochemical, and imaging characterization of acute lung injury in mice. , 2005, American journal of respiratory and critical care medicine.

[21]  J. Bates,et al.  injurious ventilation in rats Pulmonary impedance and alveolar instability during , 2005 .

[22]  G. Laurent,et al.  Pulmonary fibrosis: searching for model answers. , 2005, American journal of respiratory cell and molecular biology.

[23]  J. Bates,et al.  Tumor Necrosis Factor–α Overexpression in Lung Disease , 2005 .

[24]  E. Ingenito,et al.  The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. , 2005, American journal of respiratory cell and molecular biology.

[25]  B Nebiyou Bekele,et al.  Murine Lung Tumor Measurement Using Respiratory-Gated Micro-Computed Tomography , 2005, Investigative radiology.

[26]  J. Bates,et al.  Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype. , 2005, American journal of respiratory and critical care medicine.

[27]  Michael E Phelps,et al.  Monitoring antiproliferative responses to kinase inhibitor therapy in mice with 3'-deoxy-3'-18F-fluorothymidine PET. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  W. Mitzner,et al.  On defining total lung capacity in the mouse. , 2004, Journal of applied physiology.

[29]  John P Mugler,et al.  Exploring lung function with hyperpolarized 129Xe nuclear magnetic resonance , 2004, Magnetic resonance in medicine.

[30]  Dianna D Cody,et al.  In vivo respiratory-gated micro-CT imaging in small-animal oncology models. , 2004, Molecular imaging.

[31]  Harvey R Herschman,et al.  Molecular Imaging: Looking at Problems, Seeing Solutions , 2003, Science.

[32]  S. Shore Modeling airway remodeling: the winner by a nose? , 2003, American journal of respiratory and critical care medicine.

[33]  P. Macklem,et al.  Airway wall remodeling: friend or foe? , 2003, Journal of applied physiology.

[34]  Louis A Gatto,et al.  Positive end-expiratory pressure after a recruitment maneuver prevents both alveolar collapse and recruitment/derecruitment. , 2003, American journal of respiratory and critical care medicine.

[35]  Ronald G Blasberg,et al.  Molecular-genetic imaging: current and future perspectives. , 2003, The Journal of clinical investigation.

[36]  S S Gambhir,et al.  Optical imaging of transferrin targeted PEI/DNA complexes in living subjects , 2003, Gene Therapy.

[37]  Jason H T Bates,et al.  Measuring lung function in mice: the phenotyping uncertainty principle. , 2003, Journal of applied physiology.

[38]  J S Petersson,et al.  Molecular imaging using hyperpolarized 13C. , 2003, The British journal of radiology.

[39]  S. Shapiro,et al.  Chronic obstructive pulmonary disease • 3: Experimental animal models of pulmonary emphysema , 2002, Thorax.

[40]  P. Sime,et al.  Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains. , 2002, American journal of respiratory cell and molecular biology.

[41]  Peter Magnusson,et al.  Quantitative measurement of regional lung ventilation using 3He MRI , 2002, Magnetic resonance in medicine.

[42]  E. Gelfand Pro: mice are a good model of human airway disease. , 2002, American journal of respiratory and critical care medicine.

[43]  C. Persson Con: mice are not a good model of human airway disease. , 2002, American journal of respiratory and critical care medicine.

[44]  J. Bates,et al.  Airway and tissue mechanics in a murine model of asthma: alveolar capsule vs. forced oscillations. , 2002, Journal of applied physiology.

[45]  R. Strieter Inflammatory Mechanisms Are Not a Minor Component of the Pathogenesis of Idiopathic Pulmonary Fibrosis , 2002 .

[46]  R. Strieter Con: Inflammatory mechanisms are not a minor component of the pathogenesis of idiopathic pulmonary fibrosis. , 2002, American journal of respiratory and critical care medicine.

[47]  B. Rice,et al.  In vivo imaging of light-emitting probes. , 2001, Journal of biomedical optics.

[48]  R. Homer,et al.  Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1 , 2001, The Journal of experimental medicine.

[49]  C. Lisboa,et al.  Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. , 2001, American journal of respiratory and critical care medicine.

[50]  G. Nieman,et al.  Altered alveolar mechanics in the acutely injured lung , 2001, Critical care medicine.

[51]  L W Hedlund,et al.  Registered 1H and 3He magnetic resonance microscopy of the lung , 2001, Magnetic resonance in medicine.

[52]  J. Fozard,et al.  Pulmonary edema induced by allergen challenge in the rat: Noninvasive assessment by magnetic resonance imaging , 2001, Magnetic resonance in medicine.

[53]  M. Fujita,et al.  Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[54]  R. Homer,et al.  Interferon γ Induction of Pulmonary Emphysema in the Adult Murine Lung , 2000, The Journal of experimental medicine.

[55]  L W Hedlund,et al.  Detection of emphysema in rat lungs by using magnetic resonance measurements of 3He diffusion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  G. Hedenstierna,et al.  Effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury. , 1998, American journal of respiratory and critical care medicine.

[57]  G. Hedenstierna,et al.  Dynamics of lung collapse and recruitment during prolonged breathing in porcine lung injury. , 1998, Journal of applied physiology.

[58]  R R Edelman,et al.  Pulmonary perfusion: Qualitative assessment with dynamic contrast‐enhanced MRI using ultra‐short TE and inversion recovery turbo FLASH , 1996, Magnetic resonance in medicine.

[59]  K. Paigen,et al.  A miracle enough: the power of mice , 1995, Nature Medicine.

[60]  W. Happer,et al.  Biological magnetic resonance imaging using laser-polarized 129Xe , 1994, Nature.

[61]  M. Lamy,et al.  The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. , 1994, American journal of respiratory and critical care medicine.

[62]  J R MacFall,et al.  MR microscopy of the rat lung using projection reconstruction , 1993, Magnetic resonance in medicine.

[63]  G. Snider,et al.  Animal models of emphysema. , 1986, The American review of respiratory disease.

[64]  H. Bachofen,et al.  Electron microscopy of rapidly frozen lungs: evaluation on the basis of standard criteria. , 1982, Journal of applied physiology: respiratory, environmental and exercise physiology.

[65]  M. Kneussl,et al.  Alpha-adrenergic receptors in human and canine tracheal and bronchial smooth muscle. , 1978, Journal of applied physiology: respiratory, environmental and exercise physiology.