scholarly journals Experimental Models of Pulmonary Fibrosis and their Translational Potential

2019 ◽  
Vol 19 (3) ◽  
pp. 95-102
Author(s):  
Adamcakova Jana ◽  
Palova Romana ◽  
Mokra Daniela
Keyword(s):  
Clinical Practice ◽  
Animal Models ◽  
Pulmonary Fibrosis ◽  
Silicon Dioxide ◽  
Fluorescein Isothiocyanate ◽  
Lung Parenchyma ◽  
Experimental Models ◽  
Lung Damage ◽  
Preclinical Testing ◽  
Novel Treatment

Abstract Pulmonary fibrosis, represented mainly by idiopathic pulmonary fibrosis, develops chronic and progressive changes in lung parenchyma with high mortality and limited therapeutic options. The aim of this review was to summarize the most common experimental models used in the research of pulmonary fibrosis. Lung damage associated with development of pulmonary fibrosis can be caused by irradiation or by instillation of bleomycin, fluorescein isothiocyanate (FITC), silicon dioxide (silica), asbestos, etc. This article reviews the characteristics of the most frequently used animal models of fibrosis, including the limitations of their use. Although none of the used animal models resembles completely the changes in human pulmonary fibrosis, similarities between them allow preclinical testing of novel treatment approaches or their combinations in the laboratory conditions before their use in the clinical practice.

scholarly journals Approaching 3R teaching in biomedical engineering

2020 ◽  
Author(s):  
Valeria Chiono
Keyword(s):  
Animal Models ◽  
Biomedical Engineering ◽  
Experimental Models ◽  
Preclinical Testing ◽  
Preclinical Trials ◽  
European Standards ◽  
Preclinical Animal Models ◽  
In Silico Models

Since its adhesion to Centro3R, Politecnico di Torino has approached 3R teaching through a new Master course, entitled “New advances in alternative preclinical trials”. This is a multidisciplinary optional course for Master students in Biomedical Engineering, with the contribution of different teachers, who are experts on different aspects of preclinical testing of biomedical devices: European Standards for preclinical experimentation; preclinical animal models; protection of animal welfare in the European legislation; the role of statistics on the application of the 3R principle; preclinical experimental models in vitro; in silico models. This contribution describes the subjects faced by the course and their importance in the context of the 3R Principle.

Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models

2020 ◽  
Vol 12 (567) ◽  
pp. eaay3724
Author(s):  
Suraj U. Hettiarachchi ◽  
Yen-Hsing Li ◽  
Jyoti Roy ◽  
Fenghua Zhang ◽  
Estela Puchulu-Campanella ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Targeted Delivery ◽  
Collagen Synthesis ◽  
Lung Parenchyma ◽  
Therapeutic Agents ◽  
Experimental Models ◽  
Pi3k Inhibitor ◽  
Lung Fibroblasts ◽  
Average Life Expectancy ◽  
Pi3k Activation

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an average life expectancy of 3 to 5 years. IPF is characterized by progressive stiffening of the lung parenchyma due to excessive deposition of collagen, leading to gradual failure of gas exchange. Although two therapeutic agents have been approved from the FDA for IPF, they only slow disease progression with little impact on outcome. To develop a more effective therapy, we have exploited the fact that collagen-producing myofibroblasts express a membrane-spanning protein, fibroblast activation protein (FAP), that exhibits limited if any expression on other cell types. Because collagen-producing myofibroblasts are only found in fibrotic tissues, solid tumors, and healing wounds, FAP constitutes an excellent marker for targeted delivery of drugs to tissues undergoing pathologic fibrosis. We demonstrate here that a low–molecular weight FAP ligand can be used to deliver imaging and therapeutic agents selectively to FAP-expressing cells. Because induction of collagen synthesis is associated with phosphatidylinositol 3-kinase (PI3K) activation, we designed a FAP-targeted PI3K inhibitor that selectively targets FAP-expressing human IPF lung fibroblasts and potently inhibited collagen synthesis. Moreover, we showed that administration of the inhibitor in a mouse model of IPF inhibited PI3K activation in fibrotic lungs, suppressed production of hydroxyproline (major building block of collagen), reduced collagen deposition, and increased mouse survival. Collectively, these studies suggest that a FAP-targeted PI3K inhibitor might be promising for treating IPF.

scholarly journals Designs for research of High Dilutons in animal models: an update

2021 ◽  
Vol 10 (35) ◽  
pp. 80-80
Author(s):  
Adrian Alecu ◽  
Romeo Brezeanu
Keyword(s):  
Clinical Practice ◽  
Animal Models ◽  
Biological Effects ◽  
Experimental Studies ◽  
Experimental Models ◽  
Daily Clinical Practice ◽  
Basic Requirement ◽  
Pharmacological Studies ◽  
High Dilutions

This article discusses the series of tests on animal experimental models carried out by our group to evaluate the effect of homeopathic preparations selected according to traditional criteria of pathogenetic similarity. Our overall experience indicates that it is not difficult to carry out experimental studies assaying homeopathic medicines in randomized placebo-controlled tests returning statistically analyzable results. The basic requirement for this purpose is to select validated experimental models. The simplest and most reliable ones are the ones arising from common daily clinical practice or those taken from classical pharmacological studies modified as to fit the goals of a homeopathic assay. By proceeding in this way it will be possible to build a sound body of evidence for the biological effects of high dilutions.

scholarly journals Pseudomonas Aeruginosa Lectins As Targets for Novel Antibacterials

Acta Naturae ◽  
2015 ◽  
Vol 7 (2) ◽  
pp. 29-41 ◽  
Author(s):  
A. V. Grishin ◽  
M. S. Krivozubov ◽  
A. S. Karyagina ◽  
A. L. Gintsburg
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Practice ◽  
Animal Models ◽  
Biofilm Formation ◽  
Specific Resistance ◽  
Experimental Models ◽  
Human Tissues ◽  
Opportunistic Pathogens ◽  
New Compounds

Pseudomonas aeruginosa is one of the most widespread and troublesome opportunistic pathogens that is capable of colonizing various human tissues and organs and is often resistant to many currently used antibiotics. This resistance is caused by different factors, including the acquisition of specific resistance genes, intrinsic capability to diminish antibiotic penetration into the bacterial cell, and the ability to form biofilms. This situation has prompted the development of novel compounds differing in their mechanism of action from traditional antibiotics that suppress the growth of microorganisms or directly kill bacteria. Instead, these new compounds should decrease the pathogens ability to colonize and damage human tissues by inhibiting the virulence factors and biofilm formation. The lectins LecA and LecB that bind galactose and fucose, as well as oligo- and polysaccharides containing these sugars, are among the most thoroughly-studied targets for such novel antibacterials. In this review, we summarize the results of experiments highlighting the importance of these proteins for P. aeruginosa pathogenicity and provide information on existing lectins inhibitors and their effectiveness in various experimental models. Particular attention is paid to the effects of lectins inhibition in animal models of infection and in clinical practice. We argue that lectins inhibition is a perspective approach to combating P. aeruginosa. However, despite the existence of highly effective in vitro inhibitors, further experiments are required in order to advance these inhibitors into pre-clinical studies.

Quantitative Microscopic Comparison of the Organization of the Lung in Transgenic Mice Expressing Transforming Growth Factor-α (TGF-α)

1996 ◽  
Vol 54 ◽  
pp. 14-15
Author(s):  
C. G. Plopper ◽  
C. Helton ◽  
A. J. Weir ◽  
J. A. Whitsett ◽  
T. R. Korfhagen
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transgenic Mice ◽  
Blood Vessels ◽  
Lung Parenchyma ◽  
Lung Maturation ◽  
Alveolar Air ◽  
Parenchymal Tissue ◽  
Air Space ◽  
Conducting Airways

A wide variety of growth factors are thought to be involved in the regulation of pre- and postnatal lung maturation, including factors which bind to the epidermal growth factor receptor. Marked pulmonary fibrosis and enlarged alveolar air spaces have been observed in lungs of transgenic mice expressing human TGF-α under control of the 3.7 KB human SP-C promoter. To test whether TGF-α alters lung morphogenesis and cellular differentiation, we examined morphometrically the lungs of adult (6-10 months) mice derived from line 28, which expresses the highest level of human TGF-α transcripts among transgenic lines. Total volume of lungs (LV) fixed by airway infusion at standard pressure was similar in transgenics and aged-matched non-transgenic mice (Fig. 1). Intrapulmonary bronchi and bronchioles made up a smaller percentage of LV in transgenics than in non-transgenics (Fig. 2). Pulmonary arteries and pulmonary veins were a smaller percentage of LV in transgenic mice than in non-transgenics (Fig. 3). Lung parenchyma (lung tissue free of large vessels and conducting airways) occupied a larger percentage of LV in transgenics than in non-transgenics (Fig. 4). The number of generations of branching in conducting airways was significantly reduced in transgenics as compared to non-transgenic mice. Alveolar air space size, as measured by mean linear intercept, was almost twice as large in transgenic mice as in non-transgenics, especially when different zones within the lung were compared (Fig. 5). Alveolar air space occupied a larger percentage of the lung parenchyma in transgenic mice than in non-transgenic mice (Fig. 6). Collagen abundance was estimated in histological sections as picro-Sirius red positive material by previously-published methods. In intrapulmonary conducting airways, collagen was 4.8% of the wall in transgenics and 4.5% of the wall in non-transgenic mice. Since airways represented a smaller percentage of the lung in transgenics, the volume of interstitial collagen associated with airway wall was significantly less. In intrapulmonary blood vessels, collagen was 8.9% of the wall in transgenics and 0.7% of the wall in non-transgenics. Since blood vessels were a smaller percentage of the lungs in transgenics, the volume of collagen associated with the walls of blood vessels was five times greater. In the lung parenchyma, collagen was 51.5% of the tissue volume in transgenics and 21.2% in non-transgenics. Since parenchyma was a larger percentage of lung volume in transgenics, but the parenchymal tissue was a smaller percent of the volume, the volume of collagen associated with parenchymal tissue was only slightly greater. We conclude that overexpression of TGF-α during lung maturation alters many aspects of lung development, including branching morphogenesis of the airways and vessels and alveolarization in the parenchyma. Further, the increases in visible collagen previously associated with pulmonary fibrosis due to the overexpression of TGF-α are a result of actual increases in amounts of collagen and in a redistribution of collagen within compartments which results from morphogenetic changes. These morphogenetic changes vary by lung compartment. Supported by HL20748, ES06700 and the Cystic Fibrosis Foundation.

METHODS FOR SIMULATION OF ACUTE BRAIN ISCHEMIA: PATHOPHYSIOLOGICAL SUBSTANTIATION OF SELECTION AND IMPORTANCE FOR CLINICAL PRACTICE

2019 ◽  
pp. 142-152
Author(s):  
Б.И. Гельцер ◽  
Э.В. Слабенко ◽  
Ю.В. Заяц ◽  
В.Н. Котельников
Keyword(s):  
Clinical Practice ◽  
Experimental Studies ◽  
Cerebrovascular Diseases ◽  
Experimental Models ◽  
Pathological Process ◽  
Ischemic Brain ◽  
Actual Clinical Practice ◽  
Acute Cerebral Ischemia ◽  
Different Types ◽  
Acute Brain Ischemia

Одним из основных требований к разработке экспериментальных моделей цереброваскулярных заболеваний является их максимальная приближенность к реальной клинической практике. В работе систематизированы данные по основным методам моделирования острой ишемии головного мозга (ОИГМ), представлена их классификация, анализируются данные о преимуществах и недостатках той или иной модели. Обсуждаются результаты экспериментальных исследований по изучению патогенеза ОИГМ с использованием различных моделей (полной и неполной глобальной, локальной и мультифокальной ишемии) и способов их реализации (перевязка артерий, клипирование, коагуляция, эмболизация и др.). Особое внимание уделяется «стабильности» последствий острого нарушения мозгового кровообращения: необратимых ишемических повреждений головного мозга или обратимых с реперфузией заданной продолжительности. Отмечается, что важное значение в этих исследованиях должно принадлежать современным методам прижизненной визуализации очагов острого ишемического повреждения, что позволяет оценивать динамику патологического процесса. Предлагаемый метод отвечает требованиям гуманного обращения с животными. Подчеркивается, что выбор релевантной модели ОИГМ определяется задачами предстоящего исследования и технологическими ресурсами научной лаборатории. Development of experimental models for acute forms of cerebrovascular diseases is essential for implementation of methods for their prevention and treatment. One of the principal requirements to such models is their maximum approximation to actual clinical practice. This review systematized major models of acute cerebral ischemia (ACI), their classification, and presented information about their advantages and shortcomings. Also, the review presented results of experimental studies on pathophysiological mechanisms of different types of modeled ACI (complete and incomplete global, local, and multifocal ischemia) and methods for creating these models (arterial ligation, clipping, coagulation, embolization, etc.). Particular attention was paid to “stability” of the consequences of acutely impaired cerebral circulation - an irreversible ischemic brain injury or a reversible injury with reperfusion of a given duration. The authors emphasized that in such studies, a special significance should be given to intravital imaging of acute ischemic damage foci using modern methods, which allow assessing the dynamics of the pathological process and meet the requirements to humane treatment of animals. The choice of a relevant ACI model is determined by objectives of the planned study and the technological resources available at the research laboratory.

scholarly journals Diagnostic and prognostic implications of 2018 guideline for the diagnosis of idiopathic pulmonary fibrosis in clinical practice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jooae Choe ◽  
Byoung Soo Kwon ◽  
Kyung-Hyun Do ◽  
Hee Sang Hwang ◽  
Jin Woo Song ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Interobserver Agreement ◽  
Usual Interstitial Pneumonia ◽  
High Specificity ◽  
Fluid Analysis ◽  
Diagnostic Certainty ◽  
Prognostic Stratification ◽  
Prognostic Implications

AbstractThe purpose of this study was to evaluate the implications of the 2018 updated guideline for the diagnosis of idiopathic pulmonary fibrosis (IPF) in clinical practice compared to 2011 guideline. This study involved 535 patients including 339 IPF and 196 non-IPF, and we retrospectively evaluated CT classifications of usual interstitial pneumonia (UIP) by two guidelines. Interobserver agreement of 2018 criteria showed moderate reliability (κ = 0.53) comparable to 2011 (κ = 0.56) but interobserver agreement for probable UIP was fair (κ = 0.40). CT pattern of indeterminate for UIP was associated with better prognosis compared with the other groups (adjusted hazard ratio [HR] = 0.36, p < 0.001). Compared to possible UIP, probable UIP demonstrated a lower positive predictive value (PPV, 62.9% vs 65.8%). In analysis of patients with CT patterns of non-definite UIP, diagnosing IPF when CT pattern showed probable UIP with lymphocyte count ≤ 15% in BAL fluid, and either male sex or age ≥ 60 years showed a high specificity of 90.6% and a PPV of 80.8% in the validation cohort. The 2018 criteria provide better prognostic stratification than the 2011 in patients with possible UIP. BAL fluid analysis can improve the diagnostic certainty for IPF diagnosis in patients with probable UIP CT pattern.

scholarly journals Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shinjini Chakraborty ◽  
Veronika Eva Winkelmann ◽  
Sonja Braumüller ◽  
Annette Palmer ◽  
Anke Schultze ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Inflammatory Responses ◽  
Experimental Models ◽  
Lung Damage ◽  
C5a Receptor ◽  
Cytokine Levels ◽  
Vitro Model

AbstractSingular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.

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