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The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function

DiGuilio et al., Experimental Lung Research, doi:10.1080/01902148.2023.2193637
Mar 2023  
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Vitamin D for COVID-19
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In Vitro study showing that TNF-α induced a multiphasic transepithelial leak in Calu-3 cell layers, and that vitamin A and vitamin D (calcitriol) were effective at reducing the barrier compromise caused by TNF-α.
Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function EFSA, EFSA (B), Galmés, Galmés (B). Vitamin D inhibits SARS-CoV-2 replication in vitro Campolina-Silva, Pickard, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections Campolina-Silva, Pickard, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression Sposito, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells Alcalá-Santiago, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway Chen, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects Gotelli, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling Wang, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-19 Saheb Sharif-Askari. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity Graydon, Oh.
Study covers vitamin A and vitamin D.
DiGuilio et al., 31 Mar 2023, peer-reviewed, 5 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperVitamin DAll
The multiphasic TNF-α-induced compromise of Calu-3 airway epithelial barrier function
Katherine M Diguilio, Elizabeth Rybakovsky, Yoongyeong Baek, Mary Carmen Valenzano, James M Mullin
Experimental Lung Research, doi:10.1080/01902148.2023.2193637
Purpose: Airway epithelial barrier leak and the involvement of proinflammatory cytokines play a key role in a variety of diseases. This study evaluates barrier compromise by the inflammatory mediator Tumor Necrosis Factor-α (TNF-α) in the human airway epithelial Calu-3 model. Methods: We examined the effects of TNF-α on barrier function in Calu-3 cell layers using Transepithelial Electrical Resistance (TER) and transepithelial diffusion of radiolabeled probe molecules. Western immunoblot analyses of tight junctional (TJ) proteins in detergent soluble fractions were performed. Results: TNF-α dramatically reduced TER and increased paracellular permeability of both 14C-D-mannitol and the larger 5 kDa probe, 14C-inulin. A time course of the effects shows two separate actions on barrier function. An initial compromise of barrier function occurs 2-4 hours after TNF-α exposure, followed by complete recovery of barrier function by 24 hrs. Beginning 48 hrs. post-exposure, a second more sustained barrier compromise ensues, in which leakiness persists through 144 hrs. There were no changes in TJ proteins observed at 3 hrs. post exposure, but significant increases in claudins-2, -3, -4, and -5, as well as a decrease in occludin were seen at 72 hrs. post TNF-α exposure. Both the 2-4 hr. and the 72 hr. TNF-α induced leaks are shown to be mediated by the ERK signaling pathway. Conclusion: TNF-α induced a multiphasic transepithelial leak in Calu-3 cell layers that was shown to be ERK mediated, as well as involve changes in the TJ complex. The micronutrients, retinoic acid and calcitriol, were effective at reducing this barrier compromise caused by TNF-α. The significance of these results for airway disease and for COVID-19 specifically are discussed.
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