Insights into Inhalation Drug Disposition: The Roles of Pulmonary Drug-Metabolizing Enzymes and Transporters

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4671 - 4671

Опубликована: Апрель 25, 2024

The past five decades have witnessed remarkable advancements in the field of inhaled medicines targeting lungs for respiratory disease treatment. As a non-invasive drug delivery route, inhalation therapy offers numerous benefits to patients, including rapid and targeted exposure at specific sites, quick onset action, bypassing first-pass metabolism, beyond. Understanding characteristics pulmonary transporters metabolizing enzymes is crucial comprehending efficient clearance processes within lungs. These are intricately linked both local systemic pharmacokinetics pharmacodynamics drugs. This review aims provide comprehensive overview literature on lung while exploring their roles exogenous endogenous substance disposition. Additionally, we identify discuss principal challenges this area research, providing foundation future investigations aimed optimizing administration. Moving forward, it imperative that research endeavors focus refining validating vitro ex vivo models more accurately mimic human system. Such will enhance our understanding processing different pathological states facilitate discovery novel approaches investigating lung-specific enzymes. deeper insight be developing effective therapies diseases, ultimately leading improved patient outcomes.

Язык: Английский

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The effects of fine particulate matter (SRM 2786) on three different 3D lung models exposed at the air-liquid interface – A comparative study

Toxicology in Vitro, Год журнала: 2024, Номер 98, С. 105841 - 105841

Опубликована: Май 8, 2024

3D cell culture models exposed at the air-liquid interface (ALI) represent a potential alternative to animal experiments for hazard and risk assessment of inhaled compounds. This study compares cocultures composed either Calu-3, A549 or HBEC3-KT lung epithelial cells, cultured together with THP-1-derived macrophages EA.hy926 endothelial in terms barrier capacity responses standard reference sample fine particulate matter (SRM 2786). High-content imaging analysis revealed similar cellular composition between different models. The cultures Calu-3 cells showed greatest capacity, as measured by transepithelial electrical resistance permeability Na-fluorescein. Mucus production was detected based on cells. Exposure SRM 2786 ALI increased cytokine release expression genes associated inflammation xenobiotic metabolism. Moreover, presence central all While produced qualitatively responses, more pronounced pro-inflammatory were observed basolateral compartment compared model, likely due their reduced lower retention secreted mediators apical compartment.

Язык: Английский

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A Monoclonal Human Alveolar Epithelial Cell Line (“Arlo”) with Pronounced Barrier Function for Studying Drug Permeability and Viral Infections

Advanced Science, Год журнала: 2023, Номер 10(8)

Опубликована: Фев. 7, 2023

Abstract In the development of orally inhaled drug products preclinical animal models regularly fail to predict pharmacological as well toxicological responses in humans. Models based on human cells and tissues are potential alternatives experimentation allowing for isolation essential processes biology making them accessible vitro. Here, generation a novel monoclonal cell line “Arlo,” derived from polyclonal alveolar epithelium lentivirus immortalized hAELVi via single‐cell printing, its characterization model building block future complex vitro is described. “Arlo” systematically compared primary epithelial (hAEpCs) line. show enhanced barrier properties with high transepithelial electrical resistance (TEER) ≈3000 Ω cm 2 difference (PD) ≈30 mV under air–liquid interface (ALI) conditions, that can be modulated. The grow polarized monolayer express genes relevant integrity homeostasis observed hAEpCs. Successful productive infection severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) proof‐of‐principle study offers an additional, attractive application beyond biopharmaceutical experimentation.

Язык: Английский

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Minimum Information for Conducting and Reporting In Vitro Intracellular Infection Assays

ACS Infectious Diseases, Год журнала: 2024, Номер 10(2), С. 337 - 349

Опубликована: Янв. 31, 2024

Bacterial pathogens are constantly evolving to outsmart the host immune system and antibiotics developed eradicate them. One key strategy involves ability of bacteria survive replicate within cells, thereby causing intracellular infections. To address this unmet clinical need, researchers adopting new approaches, such as development novel molecules that can penetrate thus exerting their antimicrobial activity intracellularly, or repurposing existing using nanocarriers (i.e., nanoantibiotics) for site-specific delivery. However, inconsistency in information reported across published studies makes it challenging scientific comparison judgment experiments future direction by researchers. Together with lack reproducibility experiments, these inconsistencies limit translation experimental results beyond pre-clinical evaluation. Minimum guidelines have been instrumental addressing challenges other fields biomedical research. Guidelines recommendations provided herein designed essential parameters be disclosed when publishing methodology results, divided into four main categories: (i) design, (ii) establishing an vitro model, (iii) assessment efficacy therapeutics, (iv) statistical assessment. These intention improve rigor while enabling quantitative comparisons studies, ultimately facilitating emerging technologies clinically viable therapies safely effectively treat

Язык: Английский

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Review of New Approach Methodologies for Application in Risk Assessment of Nanoparticles in the Food and Feed Sector: Status and Challenges

EFSA Supporting Publications, Год журнала: 2024, Номер 21(9)

Опубликована: Сен. 1, 2024

Abstract New Approach Methodologies (NAMs), broadly understood to include in silico, chemico, vitro and ex vivo methods, show great potential advancing risk assessment albeit their regulatory implementation is lagging. The EFSA Guidance on of nanomaterials (EFSA Nano‐RA) suggests nano‐specific best achieved through Integrated Approaches Testing Assessment (IATAs) with NAMs as the first choice generate new information. Integrating promises several advantages such a better human focus, more detailed insights into molecular mechanisms higher efficacy. However, applying NMs also poses considerable challenges issues related dispersion stability, dosimetry, agglomeration, dissolution, transformations or assay interferences. Significant efforts are being undertaken by standardisation organisations research projects establish various for NMs. Here thorough review provided covering that will be potentially useful food feed sector. It follows structure Nano‐RA expands it, where needed, support decision‐making selection NM assessment. begins an overview NAM‐frameworks, followed description individual including those relevant physicochemical characterisation, exposure hazard toxicodynamics toxicokinetics. focus concerning degradation/dissolution, genotoxicity, cytotoxicity, oxidative stress, (pro‐)inflammation, barrier integrity important endpoints initial screening according framework. As result, total 267 nano‐relevant NAMs, mostly “not validated” (with few notable exceptions), were included this review. Validation notwithstanding, could already prove reliable NMs, especially integrated approaches.

Язык: Английский

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A Novel In Vitro Primary Human Alveolar Model (AlveolAir™) for H1N1 and SARS-CoV-2 Infection and Antiviral Screening

Microorganisms, Год журнала: 2025, Номер 13(3), С. 572 - 572

Опубликована: Март 3, 2025

Lower respiratory infections, mostly caused by viral or bacterial pathogens, remain a leading global cause of mortality. The differences between animal models and humans contribute to inefficiencies in drug development, highlighting the need for more relevant predictive, non-animal models. In this context, AlveolAir™, fully primary vitro 3D human alveolar model, was characterized demonstrated sustained presence type I (ATI) II (ATII) cells. This model exhibited functional barrier over 30-day period, evidenced high transepithelial electrical resistance (TEER). These findings were further validated tight junctions’ confocal microscopy low permeability Lucifer yellow, confirming AlveolAir™ as robust platform transport assays. Additionally, successful infections with H1N1 SARS-CoV-2 viruses achieved, antiviral treatments Baloxavir Remdesivir, respectively, effectively reduced replication. Interestingly, both infected only epithelial layer without replicating endothelial indicate assessing toxicity xenobiotics evaluating efficacy novel therapies.

Язык: Английский

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Advanced in vitro systems available for respiratory toxicology

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Characterization of Commercially Available Human Primary Alveolar Epithelial Cells

American Journal of Respiratory Cell and Molecular Biology, Год журнала: 2024, Номер 70(5), С. 339 - 350

Опубликована: Янв. 11, 2024

In vitro lung research requires appropriate cell culture models that adequately mimic in vivo structure and function. Previously, researchers have extensively utilized commercially available easily expandable A549 NCI-H441 cells which replicate some yet not all features of alveolar epithelial cells. Specifically, these are often restricted by terminally altered expression while lacking important characteristics. Of late, human primary (hPAEpC) become available, but so far poorly specified. Here, we applied a comprehensive set technologies to characterize their morphology, surface marker expression, transcriptomic profile, functional properties. At optimized seeding numbers 7,500 per cm2 growth at gas-liquid interface, hPAEpC formed regular monolayers with tight junctions amiloride-sensitive transepithelial ion transport. Electron microscopy revealed lamellar body microvilli formation characteristic for type II Protein single analyses I markers, data failed detect NKX2-1, an transcriptional regulator differentiation. With increasing passage number, transdifferentiated towards alveolar-basal intermediates characterized as SFTPC-, KRT8high KRT5- spite marked changes transcriptome function passaging, UMAP plots did reveal major shifts clusters permeability was unaffected. The present work delineates conditions, cellular characteristics properties hPAEpC. may provide useful model system studies on drug delivery, barrier function, transport vitro.

Язык: Английский

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Lack of racial and ethnic diversity in lung cancer cell lines contributes to lung cancer health disparities

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Ноя. 1, 2023

Lung cancer is the leading cause of death in United States and worldwide, a major source health disparities. cell lines provide key

Язык: Английский

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A stretchable human lung‐on‐chip model of alveolar inflammation for evaluating anti‐inflammatory drug response

Bioengineering & Translational Medicine, Год журнала: 2024, Номер 10(1)

Опубликована: Сен. 5, 2024

Abstract This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response the alveoli that may contribute to reduction of animal testing pre‐clinical stage development. The is based on alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from THP‐1 line, creating physiological biological microenvironment. To mimic three‐dimensional architecture and dynamic expansion relaxation air‐blood‐barrier, they are grown stretchable microphysiological lung‐on‐chip. For validating model, three different protocols have been developed demonstrate clinically established effect glucocorticoids reduce certain inflammatory markers after pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) simulate LPS‐induced acute lung injury measured best cytokine IL‐6 release; (2) at ALI (air‐liquid interface) investigate aerosolized treatment, chemokine IL‐8 (3) combination cytokines TNFα IFNγ critical storm leading barrier disruption, where eventual weakening or protection can be measured. In all cases, presence appeared crucial mediating changes epithelium. induction led independently stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential modeling relevant outcome disruption upon TNFα/IFNγ‐induced inflammation.

Язык: Английский

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