What is the clinical spectrum of Idiopathic Pulmonary Fibrosis?
Idiopathic pulmonary fibrosis (IPF) is an idiopathic lung disorder that affects the interstitial space located between the alveoli and capillary endothelium. The interstitial space facilitates the diffusion of oxygen from the alveoli into the pulmonary capillaries, and carbon dioxide from the capillaries into the alveoli.
Pathological characteristics of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. Chronic inflammation and fibrosis results in thickening of the interstitium, vascular remodeling, and impaired gas exchange, producing progressive symptoms of shortness of breath (dyspnea) and a dry, nonproductive cough.
IPF is heterogenous in its clinical manifestations, comorbidities, prognoses, and responses to treatments. Only about 20% of individuals with IPF are estimated to survive without any treatment, underscoring the need for effective therapeutic solutions.
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What do we know about the etiology of Idiopathic Pulmonary Fibrosis?
Although the precise mechanisms of IPF are not yet fully elucidated, findings from human studies suggest that IPF results from a combination of multiple risk factors, including advanced age, lifestyle, genetic predisposition, exposure to cigarette smoke, air pollution, viral infections, and occupational hazards related to asbestos, silica and other irritants.
The leading theory is that repeated injury to the alveolar epithelium activates immune responses and pro-fibrotic signals, which drive inflammation, epithelial cell activation, and ultimately lead to fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix (ECM) deposition .
The individual-specific genetic background weighs significantly in the risk of developing IPF, since genetic risk variants in aggregate are believed to account for at least 28% of the etiology of IPF. Thousands of so far identified rare variants associated with IPF are typically linked to telomerase maintenance, surfactant protein function, cell-cell adhesion, alveolar epithelial integrity, lung development, inflammatory processes and other processes that intervene in lung homeostasis and response to lung injury.
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How similar are human and animal respiratory systems?
Below are some of the examples of inter-species differences likely to have an impact on the face, construct, and predictive validity of animal models of IPF.
Species-specific differences in anatomy and function of the respiratory system
Human-specific features of the respiratory tract anatomy confer unique susceptibility and risk for damage of respiratory function. The features that distinguish humans from commonly employed model organisms, such as rodents, include vertical airways, length of trachea, presence of respiratory bronchioles, airway architecture, size of alveoli, and thickness of the blood-gas barrier.
Species-specific differences in the respiratory tract clearance mechanisms
Environmental exposure to pollutants, chemicals, virus and bacteria can cause alveolar epithelial injury and inflammatory responses that can lead to fibrotic remodeling. The lower speed of mucociliary clearance in rodents and the absence of submucosal gland-derived mucus secretion in rodent bronchi is likely to contribute to divergences in pathophysiology between IPF patients and animal models of IPF.
Species-specific differences in metabolizing enzymes of the respiratory tract
The inter-species differences in susceptibility to environmental toxicants and IPF pathophysiology can only be amplified by species-specific differences in types and levels of expression of metabolizing enzymes. For instance in rats, the most commonly used species in respiratory toxicity testing, the olfactory epithelium that contains specialized enzymes, such as CYPP450, covers approximately 50% of the anatomical space within the nasal cavity, over 15 times more than in humans, leading to a much more efficient metabolization of certain compounds compared to humans.
Species-specific differences in the immune system of the respiratory tract
The fact that human, but not rodent, alveoli include intravascular macrophages, is also likely to affect the ability of rodent models to faithfully recapitulate human IPF, since intravascular macrophages play a key role in vascular inflammation and fibrotic remodelling, particularly through their influence on endothelial integrity and fibroblast activation.
Beyond this feature, there are numerous differences between mice and humans in both innate and adaptive immunity. In the context of modeling IPF in mice, this also means that mouse models may not replicate the upregulation of genes associated with fibrosis and the complex interactions between fibroblasts and immune cells, limiting their ability to mimic IPF progression.
Species-specific differences in genetic and gene expression regulation
Humans differ from other species in terms of gene sequence, function and regulation, with repercussions on susceptibility to diseases. For instance, in IPF patients the dysregulation of the balance between metalloproteinases and anti-metalloproteinases plays an important role in the pathogenesis of IPF. However, the putative murine orthologue of MMP1, Mmpla, does not seem to play a similar airway remodeling role in mice. The mouse Mmpla is less expressed in normal tissues and shows low identity with 58% of identical amino acids, probably due to an evolutionary divergence and adaptation to a different environment.
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Face validity - How well do animal models replicate the human disease phenotype?
In 2017, an official American thoracic Society Workshop Report has recommended mice as the first-line animal model for preclinical trials of pulmonary fibrosis therapies. Rats were considered as a subsequent option. In contrast to certain species such as horses, dogs, and cats, mice and rats do not naturally suffer from pulmonary fibrosis. Over decades of research, a diverse set of strategies was employed to artificially induce IPF in animals, including through administration of bleomycin (BLM), fluorescein isothiocyanate (FITC), lipopolysaccharides, cadmium chloride, and Nickel ions, gene editing, and viral/bacterial infections.
However, owing in great part to above mentioned species-specific differences, the experimentally-induced IPF-like phenotype differs substantially from human IPF. For example, in BLM- and FITC-induced animal models of IPF, fibrosis tends to be diffuse and does not manifest in fibroblastic loci that in human IPF emerge over time as sites of active fibrogenesis.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of the human disease?
The complex interaction between causative factors of IPF, including genetic variants, comorbidities, lifestyle and environmental pollutants cannot be recapitulated in animals. Differences between complex combinations of triggering factors in humans and experimental induction methods in animals, combined with above described species-specific differences, are likely to produce divergent mechanisms of pulmonary fibrosis.
For instance, the commonly employed BLM induction method causes DNA strand breaks and oxidative stress. However, human IPF is not caused by DNA damage or oxidative stress alone, and apart from lung toxicants, its multifactorial etiology also involves aberrant wound healing, immune dysregulation, and genetic predisposition.
Genetic predisposition to IPF involves a complex interplay of common and rare variants, with a high inter-individual heterogeneity, leading to distinct molecular subtypes. However, human and patient-specific combinations of genetic variants related to IPF are virtually impossible to reproduce in model organisms, due to fundamental differences in genetics.
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Predictive validity - How well do animal models predict safety and efficacy of therapies in patients?
Over the last four decades, numerous pharmaceutical compounds have been shown to inhibit fibrosis in animal models of IPF. Out of 240 experimental studies of antifibrotic compounds between 1980 and 2006 that had shown promising results in IPF rodent models, none could repair the injured lung tissues in IPF patients.
To date, there is no cure for IPF, and the clinically applied anti-fibrotic drugs, such as pirfenidone and nintedanib, can help manage the symptoms or slow down the progression of IPF but, unfortunately, do not improve survival of IPF patients. Consequently, development of disease-modifying therapies for IPF remains an urgent unmet need.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical - Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of the human disease?
Owing to human-specific lung anatomy, physiology and immunology and patient-specific genetic background, comorbidities, lifestyle and environment, animal models of IPF cannot recapitulate the clinically heterogeneity of IPF symptoms, fibrosis progression and responses to treatments.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder characterized by lung fibrosis that causes symptoms of shortness of breath and cough. IPF has a generally poor prognosis, with an average survival rate after diagnosis of 3 to 5 years, and an increasing number of deaths worldwide. It is a clinically heterogenous condition, believed to be caused by a combination of advanced age, lifestyle, genetic predisposition, and exposure to environmental irritants.
Experimental induction of IPF causes severe suffering in animals. Yet, no animal model can faithfully recapitulate the human IPF phenotype and underlying mechanisms. As a result of decades-long reliance on animal research, there is no available treatment that reverses lung fibrosis and improves survival of IPF patients.
The unmet need for disease-modifying therapies for IPF can be addressed by human-based in vitro methods, that provide an opportunity to investigate patient-specific IPF mechanisms and design personalized therapies.
How is Human-Based In Vitro the Answer to Advance Biomedical Research into Idiopathic Pulmonary Fibrosis
This section examines both established and emerging ways in which human-based in vitro technologies can be used to advance our understanding of idiopathic pulmonary fibrosis. It outlines how these models are currently applied to advance research and develop new drugs, while also offering suggestions for expanding these approaches. These examples include the use of patient-derived cells in a cyclic stretch mini-lung model to mimic the pulmonary alveolar–capillary barrier, exposure of lung tissues to toxicants to dissect the impact of risk factors, and leveraging organ-on-a-chip microfluidic systems to assess the effect of drug candidates on molecular and cellular drivers of pulmonary fibrosis.
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