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The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery.

ABSTRACT: Lung fibrosis is a complex process, with unknown underlying mechanisms, involving various triggers, diseases and stimuli. Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation. Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing interstitial lung disease (fILD), characterised by a notably high mortality. Unfortunately, effective treatments for advanced fILD, and especially IPF and non-IPF progressive fibrosing phenotype ILD, are still lacking. The development of pharmacological therapies faces challenges due to limited knowledge of fibrosis pathogenesis and the absence of pre-clinical models accurately representing the complex features of the disease. To address these challenges, new model systems have been developed to enhance the translatability of preclinical drug testing and bridge the gap to human clinical trials. The use of two- and three-dimensional in vitro cultures derived from healthy or diseased individuals allows for a better understanding of the underlying mechanisms responsible for lung fibrosis. Additionally, microfluidics systems, which replicate the respiratory system's physiology ex vivo, offer promising opportunities for the development of effective therapies, especially for IPF.

SUBMITTER: Kolanko E

PROVIDER: S-EPMC10792439 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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The evolution of <i>in vitro</i> models of lung fibrosis: promising prospects for drug discovery.

Kolanko Emanuel E Cargnoni Anna A Papait Andrea A Silini Antonietta Rosa AR Czekaj Piotr P Parolini Ornella O

European respiratory review : an official journal of the European Respiratory Society 20240117 171

Lung fibrosis is a complex process, with unknown underlying mechanisms, involving various triggers, diseases and stimuli. Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation. Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing interstitial lung disease (fILD), characterise ...[more]

PMID: 38232990

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Project description:BackgroundRespiratory diseases are the 2nd leading cause of death globally. The current treatments for chronic lung diseases are only supportive. Very few new classes of therapeutics have been introduced for lung diseases in the last 40 years, due to the lack of reliable lung models that enable rapid, cost-effective, and high-throughput testing. To accelerate the development of new therapeutics for lung diseases, we established two classes of lung-mimicking models: (i) healthy, and (ii) diseased lungs - COPD.MethodsTo establish models that mimic the lung complexity to different extents, we used five design components: (i) cell type, (ii) membrane structure/constitution, (iii) environmental conditions, (iv) cellular arrangement, (v) substrate, matrix structure and composition. To determine whether the lung models are reproducible and reliable, we developed a quality control (QC) strategy, which integrated the real-time and end-point quantitative and qualitative measurements of cellular barrier function, permeability, tight junctions, tissue structure, tissue composition, and cytokine secretion.ResultsThe healthy model is characterised by (i) continuous tight junctions, (ii) physiological cellular barrier function, (iii) a full thickness epithelium composed of multiple cell layers, and (iv) the presence of ciliated cells and goblet cells. Meanwhile, the disease model emulates human COPD disease: (i) dysfunctional cellular barrier function, (ii) depletion of ciliated cells, and (ii) overproduction of goblet cells. The models developed here have multiple competitive advantages when compared with existing in vitro lung models: (i) the macroscale enables multimodal and correlative characterisation of the same model system, (ii) the use of cells derived from patients that enables the creation of individual models for each patient for personalised medicine, (iii) the use of an extracellular matrix proteins interface, which promotes physiological cell adhesion and differentiation, (iv) media microcirculation that mimics the dynamic conditions in human lungs.ConclusionOur model can be utilised to test safety, efficacy, and superiority of new therapeutics as well as to test toxicity and injury induced by inhaled pollution or pathogens. It is envisaged that these models can also be used to test the protective function of new therapeutics for high-risk patients or workers exposed to occupational hazards.

Project description:At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5-10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2-6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.

Project description:BACKGROUND:The MinION Access Program (MAP, 2014-2016) allowed selected users to test the prospects of long nanopore reads for diverse organisms and applications through the rapid development of improving chemistries. In 2014, faced with a fragmented Illumina assembly for the chloroplast genome of the green algal holobiont Caulerpa ashmeadii, we applied to the MAP to test the prospects of nanopore reads to investigate such intricacies, as well as further explore the hologenome of this species with native and hybrid approaches. RESULTS:The chloroplast genome could only be resolved as a circular molecule in nanopore assemblies, which also revealed structural variants (i.e. chloroplast polymorphism or heteroplasmy). Signal and Illumina polishing of nanopore-assembled organelle genomes (chloroplast and mitochondrion) reflected the importance of coverage on final quality and current limitations. In hybrid assembly, our modest nanopore data sets showed encouraging results to improve assembly length, contiguity, repeat content, and binning of the larger nuclear and bacterial genomes. Profiling of the holobiont with nanopore or Illumina data unveiled a dominant Rhodospirillaceae (Alphaproteobacteria) species among six putative endosymbionts. While very fragmented, the cumulative hybrid assembly length of C. ashmeadii's nuclear genome reached 24.4 Mbp, including 2.1 Mbp in repeat, ranging closely with GenomeScope's estimate (> 26.3 Mbp, including 4.8 Mbp in repeat). CONCLUSION:Our findings relying on a very modest number of nanopore R9 reads as compared to current output with newer chemistries demonstrate the promising prospects of the technology for the assembly and profiling of an algal hologenome and resolution of structural variation. The discovery of polymorphic 'chlorotypes' in C. ashmeadii, most likely mediated by homing endonucleases and/or retrohoming by reverse transcriptases, represents the first report of chloroplast heteroplasmy in the siphonous green algae. Improving contiguity of C. ashmeadii's nuclear and bacterial genomes will require deeper nanopore sequencing to greatly increase the coverage of these larger genomic compartments.

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The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery.

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The evolution of <i>in vitro</i> models of lung fibrosis: promising prospects for drug discovery.

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