New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome

Zuttion, Marilia Sanches Santos Rizzo; Moore, Sarah Kathryn Littlehale; Chen, Peter C.; Beppu, Andrew; Hook, Jaime

doi:10.3390/biom12091273

Cited by 13 publications

(9 citation statements)

References 186 publications

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“…In particular, alveolar epithelial cells covering the distal airspace act as a gateway keeper for the systemic circulation of inhaled particles. Hence, a complex mixture of AT1 and AT2 cells is required to accurately model the alveoli in vitro ( Sanches-Zuttion et al, 2022 ). In addition, immune cells like macrophages play a vital role for triggering a proper inflammatory cascade in response to infection ( Artzy-Schnirman et al, 2021 ) as well as nebulized toxicants ( Ji et al, 2018 ) in the alveoli.…”

Section: Introductionmentioning

confidence: 99%

A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip

et al. 2023

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Prolonged exposure to environmental respirable toxicants can lead to the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and fibrosis. The limited number of FDA-approved inhaled drugs for these serious lung conditions has led to a shift from in vivo towards the use of alternative in vitro human-relevant models to better predict the toxicity of inhaled particles in preclinical research. While there are several inhalation exposure models for the upper airways, the fragile and dynamic nature of the alveolar microenvironment has limited the development of reproducible exposure models for the distal lung. Here, we present a mechanistic approach using a new generation of exposure systems, the Cloud α AX12. This novel in vitro inhalation tool consists of a cloud-based exposure chamber (VITROCELL) that integrates the breathing AXLung-on-chip system (AlveoliX). The ultrathin and porous membrane of the AX12 plate was used to create a complex multicellular model that enables key physiological culture conditions: the air-liquid interface (ALI) and the three-dimensional cyclic stretch (CS). Human-relevant cellular models were established for a) the distal alveolar-capillary interface using primary cell-derived immortalized alveolar epithelial cells (AXiAECs), macrophages (THP-1) and endothelial (HLMVEC) cells, and b) the upper-airways using Calu3 cells. Primary human alveolar epithelial cells (AXhAEpCs) were used to validate the toxicity results obtained from the immortalized cell lines. To mimic in vivo relevant aerosol exposures with the Cloud α AX12, three different models were established using: a) titanium dioxide (TiO2) and zinc oxide nanoparticles b) polyhexamethylene guanidine a toxic chemical and c) an anti-inflammatory inhaled corticosteroid, fluticasone propionate (FL). Our results suggest an important synergistic effect on the air-blood barrier sensitivity, cytotoxicity and inflammation, when air-liquid interface and cyclic stretch culture conditions are combined. To the best of our knowledge, this is the first time that an in vitro inhalation exposure system for the distal lung has been described with a breathing lung-on-chip technology. The Cloud α AX12 model thus represents a state-of-the-art pre-clinical tool to study inhalation toxicity risks, drug safety and efficacy.

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Section: Introductionmentioning

confidence: 99%

A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip

et al. 2023

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“…Due to the absence of this reflex in COVID-19 infection, elastic fibers of the lungs become strained and damaged due to enlarged lung volumes. As a result of injury, alveolar micromechanics and barrier functions may be disrupted in patients, resulting in ARDS [56] [57].…”

Section: Dominant Sympathovagal Response In Covid-19mentioning

confidence: 99%

Modulation of Respiratory Neural Drive by Physiological Loads in COVID-19 Patients with Dyspnea

Crasta,

Alam,

Lakhani

2023

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COVID-19 patients often experience dyspnea due to several factors. The underlying unique pathophysiology of dyspnea in is not yet fully understood, but it is believed to be related to a combination of respiratory, cardiovascular, and neuromuscular factors. Hypoxemia is considered one of the key symptoms of COVID-19. This affects the respiratory drive, which determines the rate, depth, and pattern of breathing. The relationship between increased ventilatory neural drive and abnormal gas exchange, particularly in the context of ventilation/perfusion (V/Q) mismatches and chemosensitivity, has gained significant attention following the COVID-19 pandemic. The ACE2 receptors allow viral entry into the lungs, leading to the loss of surfactant, hypoxic vasoconstriction, and intrapulmonary shunting that may result in a V/Q mismatch. Additionally, acidosis, hypercapnia, elevated 2,3-diphosphoglycerate levels and fever may shift the oxygen diffusion curve rightward, lowering arterial oxygen saturation levels and triggering ventilatory responses. This paper examines how physio pathological factors such as altered gas diffusion, chemosensory feedback, V/Q ratios, altered compliance, arterial blood gases, and respiratory muscle dysfunction in these patients affect ventilatory drive. A review of the published literature was also conducted to determine the mechanism of dyspnea. To ensure appropriate gas exchange, individuals need to augment their minute ventilation (VE) when physiological dead space is elevated. This serves as a compensatory mechanism to counteract the effects of compromised gas exchange and keep adequate oxygenation throughout the body. The respiratory centers may experience dysregulation due to the impact of the virus on the respiratory system, which could affect the rhythm-generating and pattern-generating signals that are vital for regulating the respiratory rate and depth of breathing effort. The cerebral cortex, in conjunction with the brain stem centers, plays a crucial role in regulating ventilation dur-

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“…The lung possesses large surface area lined with thin alveolar epithelium, pulmonary surfactant (PS), and high permeable and considerable vascularization, and these structural characteristics are closely related to the inhaled delivery of therapeutics to the lung . In particular, PS is a mixture of lipids (∼90%) and proteins (∼10%) which is synthesized by type II alveolar cells and secreted into the alveolar space to reduce the surface tension in the alveoli air–liquid interspace, thus preventing alveolar collapse . While the inhaled administration of therapeutics allows their efficient localization to the distal lung, the successful delivery of targeted materials often limited by a thin barrier composed of PS and optimal concentration of therapeutics is not effectively maintained at the level of alveolar epithelium. , Hydrophobic PS proteins B and C (PSP-B and PSP-C) incorporated in the vesicles are responsible for maintaining the mechanical integrity of PS layer in the dynamic environment by modulating the fusion and spreading of PS lipids .…”

Section: Introductionmentioning

confidence: 99%

Inhalation Delivery of Interferon-λ-Loaded Pulmonary Surfactant Nanoparticles Induces Rapid Antiviral Immune Responses in the Lung

Gil,

Oh,

Lee

et al. 2024

ACS Appl. Mater. Interfaces

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The interferon-λ (IFN-λ)-regulated innate immune responses in the airway expand our understanding toward antiviral strategies against influenza A virus (IAV). The application of IFN-λ as mucosal antiviral therapeutic is still challenging, and advanced research will be necessary to achieve more efficient delivery of recombinant IFN-λs to the damaged respiratory mucosa. In this study, we examine the capability of IFN-λ to stimulate the innate immune response, promoting the swift elimination of IAV in the lungs. Additionally, we develop IFN-λ-loaded nanoparticles incorporated into pulmonary surfactant for inhalation therapy aimed at treating lung infections caused by IAV. We found that inhaled delivery of IFNλ-PSNPs significantly restricted IAV replication in the lungs from 3 days after infection (dpi), and IAV-caused lung histopathologic findings were completely improved in response to IFNλ-PSNPs. More significant and rapid attenuation of viral RNA was observed in the lung of mice with inhaled delivery of IFNλ-PSNPs compared to mice with recombinant IFN-λs. Inhalation treatment of IFNλ-PSNPs to IAV-infected mice can result in the increase of monocyte frequency in concert with restoration of T and B cells composition. Furthermore, the transcriptional profiles of monocytes shifted toward heightened IFN responses following IFNλ-PSNP treatment. These results imply that IFN-λ could serve as a robust inducer of innate immunity in the lungs against IAV infection, and inhalation of IFN-λs encapsulated in PSNPs effectively resolves lung infections caused by IAV through rapid viral clearance. PSNPs facilitated improved delivery of IFN-λs to the lungs, triggering potent antiviral immune responses upon IAV infection onset.

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New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome

Cited by 13 publications

References 186 publications

A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip

A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip

Modulation of Respiratory Neural Drive by Physiological Loads in COVID-19 Patients with Dyspnea

Inhalation Delivery of Interferon-λ-Loaded Pulmonary Surfactant Nanoparticles Induces Rapid Antiviral Immune Responses in the Lung

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