Paracellular permeability and tight junction regulation in gut health and disease

Horowitz, Arie; Chánez-Paredes, Sandra; Haest, Xenia; Turner, Jerrold R.

doi:10.1038/s41575-023-00766-3

Cited by 155 publications

(95 citation statements)

References 300 publications

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“…Moreover, TNF-α is a key proinflammatory cytokine that plays a central role in the initiation and propagation of inflammatory responses. Regeneration of the gut mucosa after TNBS treatment involves the repair of these key components, making them relevant targets for our study. , According to the qPCR data, as shown in Figure B, after TNBS treatment, Muc-2 mRNA expression was significantly ( p ≤ 0.001) diminished as compared to healthy controls. However, treatment with P(NIPAM- co -NTBAM)-HA or P(NIPAM- co -NTBAM)-HA-ePRDL significantly ( p ≤ 0.01 and p ≤ 0.001, respectively) enhanced the Muc-2 expression in colon tissues in comparison to TNBS-damaged colon tissues.…”

Section: Resultsmentioning

confidence: 98%

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device

Mairal,

Mehrotra,

Kumar

et al. 2024

ACS Appl. Mater. Interfaces

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Impairment of intestinal epithelium is a typical feature of inflammatory bowel disease (IBD) that causes leakage of bacteria and antigens from the intestinal lumen and thus results in persistent immune activation. Hence, healing and regeneration of the damaged gut mucosa is a promising therapeutic approach to achieve deep remission in IBD. Currently, available systemic therapies have moderate effects and are often associated with numerous side effects and malignancies. In this study, we aimed to develop a topical therapy by chemically conjugating a temperature-responsive polymer, i.e., poly(N-isopropylacrylamide), along with hyaluronic acid to obtain a sprayable therapeutic formulation that upon colon instillation adheres to the damaged gut mucosa due to its temperature-induced phase transition and mucoadhesive properties. An ex vivo adhesion experiment demonstrates that this therapeutic formulation forms a thin physical coating on the mucosal lining at a physiological temperature within 5 min. Physicochemical characterization of (P(NIPAM-co-NTBAM)-HA) established this formulation to be biocompatible, hemocompatible, and non-immunogenic. Prednisolone was encapsulated within the polymer formulation to achieve maximum therapeutic efficacy in the case of IBD-like conditions as assessed in a custom-fabricated perfusion-based ex vivo model system. Histological analysis suggests that the prednisolone-encapsulated polymer formulation nearly restored the mucosal architecture after 2,4,6trinitrobenzenesulfonic acid-induced damage. Furthermore, a significant (p ≤ 0.001) increase in mRNA levels of Muc-2 and ZO-1 in treated groups further confirmed the mucosal epithelial barrier restoration.

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Section: Resultsmentioning

confidence: 98%

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device

Mairal,

Mehrotra,

Kumar

et al. 2024

ACS Appl. Mater. Interfaces

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“…S5I, S5J). These data suggest that PGE2 is critical for the IAF-induced barrier disruption phenotype, but additional factors may also be involved ( 54 ).…”

Section: Resultsmentioning

confidence: 99%

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling

Dong,

Johnson,

Ruan

et al. 2023

Preprint

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Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed anin vitromodel whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFsin vivo. When co-cultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid swelling and barrier disruption due to swelling and rupture of individual epithelial cells. Epithelial cells co-cultured with IAFs also exhibit increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated through a paracrine pathway involving prostaglandin E2 (PGE2) and the PGE2 receptor EP4, leading to PKA-dependent activation of the CFTR chloride channel. Importantly, EP4-specific chemical inhibitors effectively prevented colonoid swelling and restored normal proliferation and genome stability of IAF-exposed epithelial cells. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a potential treatment to mitigate inflammation-associated epithelial injury.TeaserInflammation-associated fibroblasts compromise colon epithelial barrier integrity and genome stability via PGE2-EP4 signaling.

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“…The differences in the findings in the current study and previous studies could be due to the differences in experimental design (direct exposure to ethanol by epithelial cells in the previous study), TGFβ1 level, and other factors produced by LF. Additionally, given that paracellular permeability in the epithelial monolayer depends not only on tight junction protein expression but also their correct localization within the plasma membrane (Horowitz et al, 2023), we speculate that the effect of ethanol‐exposed fibroblasts on ZO‐1 membrane localization is sufficient to significantly alter tight junction function by disrupting ZO‐1/claudins/occludin interaction (Lynn et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

Ethanol‐exposed lung fibroblasts cause airway epithelial barrier dysfunction

Sueblinvong,

Fan,

Hart

et al. 2023

Alcohol: Clinical and Experimental Research

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BackgroundChronic alcohol ingestion predisposes to lung injury and disrepair during sepsis. Our previous studies outlined roles for TGFβ1 and GM‐CSF in epithelial barrier homeostasis and how alcohol perturbs their expression and signaling. Here we hypothesize that ethanol‐exposed lung fibroblasts (LF) are a source of dysregulated TGFβ1 and GM‐CSF and thereby alter airway epithelial barrier function.MethodsHuman or rat LF were cultured ± ethanol for 2 weeks and then co‐cultured with human or rat airway epithelial cells (AEC) seeded on Transwell permeable supports. In selected groups, a TGFβ1 receptor type 1 (TGFβR1) inhibitor (SB431542) or a TGFβ1 neutralizing antibody was applied. Transepithelial electrical resistance (TER) was measured prior to co‐culture and on day 5 of co‐culture. AEC were then analyzed for the expression of selected tight junction and mesenchymal proteins, and Transwell membranes analyzed by immunofluorescence microscopy for ZO‐1 expression and localization. TGFβ1 and GM‐CSF levels in conditioned media from the co‐cultures were quantified by ELISA.ResultsAEC co‐cultured with ethanol‐exposed LF (ELF) had a significant reduction in TER and corresponding decreases in ZO‐1 expression, whereas collagen type 1A1 and α‐smooth muscle actin protein expression were increased. In parallel, activated TGFβ1 levels were increased, whereas GM‐CSF levels were decreased, in conditioned media from the ELF + AEC co‐cultures. Notably, all these effects of ELF on the AEC were prevented by blocking TGFβ1 activity.ConclusionsPrior ethanol exposure of LF induces barrier dysfunction in naïve AEC in a paracrine fashion through activation of TGFβ1 signaling and suppression of GM‐CSF. These experimental findings provide a potential mechanism by which chronic alcohol ingestion impairs airway epithelial integrity and renders individuals susceptible to lung injury.

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Paracellular permeability and tight junction regulation in gut health and disease

Cited by 155 publications

References 300 publications

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling

Ethanol‐exposed lung fibroblasts cause airway epithelial barrier dysfunction

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