LRRI’s national and international reputation in aerosol science, respiratory physiology, COPD, lung cancer, infectious disease, inhalation drug delivery, asthma, and respiratory immunology programs, as well as our successful scientific partnerships, grantsmanship, publication record, and prominence on national biomedical committees have resulted in a record number of clients from very diverse sources. LRRI has been highly competitive in all of the above-mentioned areas and will continue to invest in scientific expertise and unique facilities to meet the needs of our clients now, as well as in the future.
Our Institute’s laboratories are available as user facilities to government, university, and private researchers, for we have mastered the complex processes of negotiating technology transfer agreements, indirect cost and pricing differences, conflicts of interest, and contract dispute resolution with academic institutions. Our ability to initiate a scientific discussion between scientists at a Lovelace institution and a University/organization and rapidly (typically within 3 weeks) consummate a formal agreement to jointly undertake the project is a unique feature of our Institute. Lovelace has established, pre-existing mechanisms already in place to quickly onboard our numerous university partners to rapidly respond to emerging operational research needs.
We partner with clients across many distinct sectors, applying our knowledge and expertise and specialized facilities and equipment to each project. Our successful partnerships include those with government agencies, commercial entities, trade associations, and academic institutions. LRRI regularly forms partnerships working for and with many academic institutions. Of particular note this past years has been the development of a unique partnership with Harvard University’s Brigham and Women’s Hospital, Division of Pulmonary Medicine that has resulted in five joint pilot studies. LRRI will collaborate with this group of Harvard scientists for new grants and contracts (especially those requiring academic M.D. principal investigators). We have developed equally productive but less formal working relationships with groups at the Johns Hopkins School of Medicine and the Denver National Jewish Medical and Research Center, as well as a number of other departments at Harvard.
LRRI offers internationally recognized expertise in aerosol science and inhalation exposure technology. These technologies can be used for research and development on aerosol generation and delivery techniques, sampling instrumentation and strategies, dosimetry of inhaled particles, characterization of radioactive particles, evaluation of decontamination technology, and personal protection strategies.
Our aerosol scientists are experienced in computer simulation, laboratory experiments, and field studies as well as in handling a broad range of airborne materials, including powders, fibers, toxic chemicals, nanomaterials, radionuclides, viruses, bacteria, and fungi. We also have BSL-3 labs to perform tests using live agents. Our facilities are unique because we can handle hazardous materials that many laboratories cannot.
LRRI provides a distinct ability to apply all of these technologies in an ABSL-3 and/or a BSL-3 setting for use with live agents. This allows our facility to work with nearly any aerosol material regardless of hazards.
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Drug Delivery and Inhalation Therapy
Characterizing the performance of nebulizers, metered dose inhalers, dry powder inhalers, and nasal sprays
Deposition patterns in realistic airway casts of the human nasal, oral, and tracheobronchial regions
Deposition pattern using gamma scintigraphy
Generation and Characterization
Design and test vapor and aerosol dissemination equipment for special test facilities
Design and test dissemination methods for simulants, live agents, chemical agents, and radioactive materials
Develop sampling strategy and instrumentation for monitoring live agents, chemical agents, and radioactive materials
Design and Test of Air Sampling Instruments
Calibration of aerosol sampling instruments including personal samplers and aerosol collectors in wind tunnel facilities
Calibrate bioaerosol detectors with simulants and live agents
Evaluate chemical detectors with simulants and chemical agents
Characterization of Radioactive Material
Dissolution rates of radioactive materials
Biokinetics of inhaled radioactive materials in lab animals
Evaluation of continuous air monitors using radioactive aerosols
Decontamination and Personal Protection Equipment
Evaluate decontamination technology using chemical/biological simulants and live agents
Evaluate respirator performance using simulants and live agents
Evaluate air cleaners, filters, and control technologies for particulate matter
Stack Monitoring in Nuclear Facilities
Perform field studies to qualify stack sampling locations Design scaled stack models and perform qualification tests following the ANSI N13.1-1999 requirements
Inhalation Studies - Exposure Facilities/Equipment
Over 30,000 square feet of specialized laboratories for conducting exposures
Over 100 whole-body exposure chambers
26 nose-only exposure chambers (24- to 96-port)
Capabilities of operating exposure systems with up to 13 whole-body chambers/room, or 6 nose-only chambers/room
Expertise in conducting nasal, oral, or whole-body inhalation exposures of laboratory animals (including rodents, dogs, non-human primates) and human subjects
Capabilities for conducting GLP-compliant inhalation toxicity studies
Acute, subchronic (90 day), chronic (18 mo up to 30 mo)
Capabilities for generating gases, vapors, powders, fibers, mists, combustion products, hazardous, toxic, and radioactive exposure atmospheres
Aerosol wind tunnels for evaluation of sampling instrumentation
Bioaerosol chambers for evaluating biodetectors and dissemination techniques
Special laboratory for testing chemical agents
BSL-3 facilities for live agents
Radiation laboratories for working with radioactive aerosols
Gamma scintigraphy laboratory
Asthma research at LRRI is conducted by groups of investigators exploring both grant- and contract-driven investigations. Investigators make full use of many of the unique capabilities available to them at LRRI, such as state-of–the-art aerosol technologies, and rodent and canine models of allergic disease.
Ted Barrett, PhD, is an NIH- and FAMRI- (Flight Attendants Medical Research Institute) funded scientist interested in 1) the role of maternal allergic status on the allergic status of the offspring (canine and murine models); 2) the role of maternal and neonatal environmental exposures on lung viral infections and the development and exacerbation of allergic asthma (canine and murine models); 3) the role of cigarette smoke and nicotine exposure on the response to pulmonary viruses and allergens (murine model). In addition, Dr. Barrett has developed unique canine models of allergic asthma, rhinitis, and dermatitis that are highly utilized by pharmaceutical companies to test new treatment modalities.
Mohan Sopori, PhD, and his collaborators, who are funded by several sources including NIH and DOD, work on two research projects related to allergy and asthma. The first delineates the mechanism by which nicotine modulates ragweed/house dust mite-induced lung inflammation, airway reactivity, mucous formation, and atopy in the Brown Norway rat model. The team is also determining the effects of nicotine on mast cell degranulation in a cell culture model. In addition, Dr. Sopori’s group has previously reported that prenatal but not postnatal exposure of mice to cigarette smoke exacerbates an allergen-induced airway hyperresponsiveness. Currently they are evaluating the role of various muscarinic receptors and cAMP in the increase in airway resistance in this model.
The scientists who participate in the Asthma Program at LRRI welcome collaborations with both academic and industry scientists.
The study of animal models of COPD and COPD exacerbation is useful for both understanding the mechanisms of this disease and for developing useful therapies. These animal models will continue to be used widely by pharmaceutical industry and individual investigators in the field to identify early markers for COPD and to test new investigational drugs based on the identification of novel mechanisms of disease.
The Lovelace Smokers Cohort (LSC), which has ~2,300 participants, was established in 2000 to study current and former smokers, and has longitudinal follow-up data. A high percentage of Hispanic participants allows studying the role of Mexican Hispanic ethnicity and the risk of developing COPD.
Clinical studies using the LSC database showed:
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The study of animal models of COPD and COPD exacerbation is useful for both understanding the mechanisms of this disease and for developing useful therapies. These animal models will continue to be used widely by pharmaceutical industry and individual investigators in the field to identify early markers for COPD and to test new drugs based on the identification of novel mechanisms of disease.
1. LRRI has expertise in measuring wood smoke concentrations in homes to study the role of wood smoke in exacerbating COPD. 2. LRRI has exposed mice to defined concentrations of wood smoke, motor vehicle exhaust, ozone, and other pollutants to determine their roles in exacerbating cigarette smoke-induced COPD. 3. LRRI has generated aerosols of various drugs and exposed the animal models to defined particle size and concentrations to determine the role of the drugs in affecting inflammation, chronic bronchitis or emphysema. 4. LRRI has a long history of testing the efficacy of numerous drugs using in vitro and in vivo animal models of COPD. Findings from these studies can then be tested in clinical trials. 5. Effect of nutrition on the development of emphysema.
View a presentation on “Rodent and Non-Human Primate Models of Emphysema and Chronic Bronchitis at LRRI.”
Why Do We Need a Nonhuman Primate Model of Smoking-Induced COPD? By Jeffrey L. Curtis and Christine M. Freeman (Adobe PDF Document) Abstract This Commentary highlights the article by Polverino et al, describing the development of a novel nonhuman primate model of cigarette smoke-induced chronic obstructive pulmonary disease. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. PMID: 25576784
Studies are ongoing that show the role of Bcl-2 family of proteins in sustaining mucous cell metaplasia in chronic diseases. These studies are determining how the Bcl-2 family of proteins regulate pulmonary inflammation.
Ongoing studies focus on understanding how gene variations in genes encoding the Bcl-2 family of proteins or those that regulate expression of these genes, may be affecting the mucus regulatory network.
Clinical research trials are a partnership and a commitment between research doctors and study participants. Trials are one of the final steps on the way to FDA drug/device approval.
Lovelace through its for-profit subsidiary, Lovelace Scientific Resources (LSR), links basic sciences to clinical research. LSR is a multidisciplinary clinical trials company specializing in Phase I through Phase IV outpatient trials.
Lovelace’s infectious disease program is actively developing and refining enhanced in vitro and in vivo capabilities to improve our understanding of the host response to infection, while developing systems to evaluate medical countermeasures against recurring and emerging biological threats. These capabilities serve to positively impact human health through the evaluation of vaccines, therapeutics and other medical countermeasures against bacterial, viral, fungal and toxin exposures.
Experimental capabilities include:
New areas of focus include:
Lovelace has developed well-characterized animal models to study influenza virus transmission and evaluate antivirals and vaccines against emerging strains of seasonal and pre-pandemic influenza. Lovelace has performed influenza transmission studies to understand how influenza is spread by aerosol. These studies involved the development of specialized isolation chambers with connecting air flow, sampling ports and particle size monitoring in order to detect the presence and viability of influenza virus, while measuring whether uninfected animals in connected chambers became infected from experimentally challenged animals.
Lovelace has formal affiliation agreements with Harvard University, The Brigham and Woman’s Hospital, and the University of New Mexico and its Health Science Center that serve as models for formal collaborative interactions with institutions of higher learning. In order to bring the latest developments in biomedical research and technologies to NHRC, Lovelace brings a significant cadre of solid relationships with basic infectious disease research universities. These universities partner with Lovelace on a very broad range of research projects, from projects involving patient-based COPD/smoking research and humanized-mouse immunology studies (Harvard) to UNM, which provides access to highly capitalized imaging technology.
The BWH Interstitial Lung Disease Program provides multi-disciplinary outpatient and inpatient care to patients affected with diverse forms of pulmonary fibrosis. Patients undergo an extensive evaluation by a pulmonologist, rheumatologist, cardiologist, and if required, a thoracic surgeon. Once diagnosis is confirmed, patients are treated with standard of care approaches and are invited to participate in clinical research trials or translational research protocols.
Dr. Rebecca Baron's CV is located here
The lung cancer program is comprised of investigators with a diversity of expertise that includes basic cell and molecular biology, genomics, epigenomics, toxicology, epidemiology, bioinformatics and statistics. All investigators have adjunct faculty appointments with departments at the University of New Mexico Health Sciences center and participate as members of Programs within the NCI Designated Comprehensive Cancer Center. LRRI scientists focus on using the basic laboratory setting to identify genes and microRNAs whose function and affect on cellular pathways may prove valuable as biomarkers for early detection, for monitoring disease recurrence, and as a targets for cancer prevention and therapy.
The program uses a multitude of tools for facilitating discovery and translation of findings into populations and patients. Cell based in vitro models involving immortalized human bronchial epithelial cells; small airway cells, fibroblasts, and macrophages are used to understand how exposures to tobacco products that include cigarette smoke, cigarillos, and electronic cigarettes induce cytotoxicity, genotoxicity, and transformation. In vitro models are also elucidating novel genes and microRNAs involved in pre-malignancy, determining how the microenvironment modifies risk for malignancy, and how aberrant signally pathways affect cell proliferation, survival, and death. Malignant human lung cancer cells lines are also used to study the effectiveness of novel targeted drug combinations.
In vitro findings are translated to in vivo studies that use animal models. The A/J mouse, a susceptible strain to induction of lung cancer by tobacco carcinogens is used to study the effect of novel therapies and nutritional supplements to impede or reverse the development of cancer. Immunocompromised nude mice and rats allow studies of human lung cancer derived tumors with regard to testing novel therapies delivered systemically or by inhalation. Finally, mice with specific genes knocked out or over expressed in the lung provide insight into the role of specific pathways in carcinogenesis and offer new insights into the effect that targeting these genes or pathways have on mitigating cancer development.
Key to moving science forward in the Lung Cancer Program is the ability to study smokers at risk for lung cancer and patients diagnosed with cancer. This unique opportunity exists because of the establishment of the Lovelace Smokers Cohort in 2000 and the New Mexico Lung Cancer Cohort in 2003 through a partnership with the University of New Mexico’s National Cancer Institute Designated Comprehensive Cancer Center. These consented participants provide exposure history, clinical data, and valuable biospecims that include blood, sputum, nasal epithelium, and tumor tissue. Members of the Lovelace Smokers cohort are also followed longitudinally with collection of biospecimens to enable studies focused on identifying risk factors for lung cancer. Integrating these two cohorts in the form of case-control studies has been integral for developing non-invasive diagnostics using sputum to identify epigenetic biomarkers that can identify subjects that are at risk for lung cancer and to provide insight regarding the role of genetic ancestry in modifying risk.
The respiratory tract is heavily innervated by both sensory (afferent) mainly via the vagus nerve and motor (efferent) components. Pulmonary neural receptors or sensors in the epithelial, mucosa, submucosa, and smooth muscle layers are sensitive to both mechanical and chemical stimuli. Stimulation activates the sensors and initiates homeostatic and defensive reflexes such as cough. Interactions of the afferent sensory nerves with inflammatory mediators and agents play a significant role in the pathogenesis, development, and treatment processes of many respiratory diseases, for examples, sleep apnea, asthma, COPD, and lung cancer, through integration of central nervous system and acting locally.
Our program focuses on the research of interactions between peripheral neural sensory afferents and the central chemoreceptors in the control of breathing, and the roles of neurogenic factors in the pathophysiology of SIDS, bronchopulmonary inflammation, respiratory viral infection, and chronic obstructive pulmonary disease.
Several animal models that mimic human diseases have been established to study the pathogenesis and to test the efficacy of treatment:
Rat Pup Model of SIDS
To mimic the smoking effects during pregnancy on the risk to develop SIDS in postnatal rats, this model is established with a full-term prenatal nicotine exposure via an implanted osmotic mini-pump drug delivering system. This model features the characteristics of human SIDS by introducing multiple SIDS risk factors: maternal smoking, male gender, critical time-window, hypoxia, potentiated pulmonary C-fibers activity, and pulmonary inflammation (by RSV infection).
Guinea Pig Model of Cough
Animal exposed to aerosol of citric acid, capsaicin, or other drugs, the evoked coughs can be quantified precisely based on the characteristic respiratory airflow patterns using plethysmography, body movement by video monitoring, sound recorded with a super-sensitive microphone and cough determined via time-frequency sound-wave analysis and synthesis. Respiratory activities (minute ventilation, breathing rate, tidal volume) are measured simultaneously. Specific airway-resistance can also be evaluated with a double-chambered plethysmograph. Efficacy of treatment can be successfully evaluated using this animal model of cough. LRRI has strong track record of generating aerosols of any type of compounds to deliver the drugs directly to the target cells.
Animal Models of Neurogenic Inflammation
Neurogenic inflammation can be induced with: 1) electrical/chemical stimulation of vagus nerve or its branches; and 2) viral infection
Animal Models of Airway Hypersensitivity
LRRI has the capability of performing safety pharmacology studies utilizing all routes of administration, including instillation and inhalation. Cardiopulmonary safety pharmacology (CPSP) addresses both the FDA-required studies for safety pharmacology (GLP studies), as well as assessing early safety and disease models for basic research. CPSP integrates best practices in pharmacology, physiology, and toxicology to identify adverse effects of drug candidates in preclinical studies and basic research aspects of disease models such as pulmonary hypertension.
CPSP capabilities include telemetry, plethysmography, ultrasound, several in vitro assays including vascular or bronchial ring or isolated lung assays, as well as molecular biology tools to investigate cardiovascular and respiratory disease models, and better understand the mechanism(s) of the disease. CPSP also investigates the cardiovascular and pulmonary physiological effects and safety of new compounds developed by our pharmaceutical clients.
In Vitro: Vascular ring function
In Vitro: Bronchial ring function and isolated lung function
Chemistry (Tier II: arterial blood gas analysis): iSTAT and Siemens Rapidpoint 405 analyzer for laboratory testing of blood gases, electrolytes, metabolites, total hemoglobin, and hemoglobin derivatives in arterial, venous, and capillary whole blood samples.
Central Nervous System
Safety Pharmacology Society http://www.safetypharmacology.org/
Society of Toxicology http://www.toxicology.org/
ICHS7A guidelines Safety Pharmacology
ICHS7B guidelines Safety Pharmacology
January 2010 Guidance Assessment of Abuse Potential of Drugs
ICHS6 guidelines Biotechnology-Derived Pharmaceuticals
ICHS4A guidelines Chronic Toxicity Testing
ICHS9 guidance Nonclinical Evaluation for Anticancer Pharmaceuticals
Fibrosis of the airway and lung tissue is the abnormal scarring of normal tissue that leads to loss of tissue and organ function. At the present time, there are no treatments for fibrotic disorders except transplant. Fibrotic scarring can occur in the airways or in the lung tissue. The severity of the fibrosis can range from mild, which is often asymptomatic, to severe, which is life limiting.
There are over 140 known causes of pulmonary fibrosis. The common theme is that they create a chronic injury in the lung tissue that leads to the scarring reaction. Pulmonary fibrosis is a common complication of radiation or chemotherapy for cancers, and limits the amounts of radiation or drugs that can be administered. In some cases, the cause is unknown (idiopathic).
LRRI is developing animal models of fibrosis to study the etiology of the disorder and the evaluation of potential therapeutics that could either prevent the fibrosis or slow its progression. Patients diagnosed with pulmonary fibrotic disorders such as idiopathic pulmonary fibrosis often have a prognosis similar to that of lung cancer patients, with a mean survival time of 12-24 months post-initial diagnosis. However, other forms of pulmonary fibrosis, such as those induced by adverse chemotherapeutic drug reactions, radiation treatment or exposure to chemical weapon agents could be responsive to appropriate therapies as treatment could begin before the fibrotic mechanisms have had sufficient time to become refractory to drug treatment.
Contract research services include animal models of drug-, radiation-, and chemical-induced forms of lung fibrosis. Both in vitro and in vivo testing of anti-fibrotic therapeutics are available.
Current Research Interests