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MPoMA protects against lung epithelial cell injury via p65 degradation
Soheun Lee1, Suh Jin Yoon1, Ji Hyun Oh1
1College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Abstract:
Numerous cases of lung injury caused by viral infection were reported during the coronavirus disease-19 pandemic. While there have been significant efforts to develop drugs that block viral infection and spread, the development of drugs to reduce or reverse lung injury has been a lower priority. This study aimed to identify compounds from a library of compounds that prevent viral infection that could reduce and prevent lung epithelial cell damage. We investigated the cytotoxicity of the compounds, their activity in inhibiting viral spike protein binding to cells, and their activity in reducing IL-8 production in lung epithelial cells damaged by amodiaquine (AQ). We identified N-(4-(4-methoxyphenoxy)-3-methylphenyl)-N-methylacetamide (MPoMA) as a non-cytotoxic inhibitor against viral infection and AQ-induced cell damage. MPoMA inhibited the expression of IL-8, IL-6, IL-1β, and fibronectin induced by AQ and protected against AQ-induced morphological changes. However, MPoMA did not affect basal IL-8 expression in lung epithelial cells in the absence of AQ. Further mechanistic analysis confirmed that MPoMA selectively promoted the proteasomal degradation of inflammatory mediator p65, thereby reducing intracellular p65 expression and p65-mediated inflammatory responses. MPoMA exerted potent anti-inflammatory and protective functions in epithelial cells against LPS-induced acute lung injury in vivo. These findings suggest that MPoMA may have beneficial effects in suppressing viral infection and preventing lung epithelial cell damage through the degradation of p65 and inhibition of the production of inflammatory cytokines.
Insights
Researchers identified MPoMA, a compound that inhibits viral infection and prevents lung epithelial cell damage. MPoMA reduces inflammatory responses by degrading the p65 protein, offering potential for treating lung injuries.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Viral infections, notably COVID-19, have caused significant lung injury.
- Drug development has prioritized antiviral therapies over treatments for lung damage.
- Identifying compounds that protect lung epithelial cells is crucial.
Purpose of the Study:
- To screen compounds for their ability to prevent viral infection and reduce lung epithelial cell damage.
- To identify novel therapeutic agents for viral-induced lung injury.
- To elucidate the mechanism of action for protective compounds.
Main Methods:
- Cytotoxicity assays were performed on a library of antiviral compounds.
- Inhibition of viral spike protein binding to cells was assessed.
- Interleukin-8 (IL-8) production in amodiaquine (AQ)-damaged lung epithelial cells was measured.
- Mechanistic studies involved analyzing proteasomal degradation of p65 and in vivo acute lung injury models.
Main Results:
- N-(4-(4-methoxyphenoxy)-3-methylphenyl)-N-methylacetamide (MPoMA) was identified as a non-cytotoxic inhibitor of viral infection and AQ-induced cell damage.
- MPoMA suppressed AQ-induced expression of IL-8, IL-6, IL-1β, and fibronectin, and prevented morphological damage.
- MPoMA selectively enhanced proteasomal degradation of p65, reducing p65-mediated inflammatory responses.
- MPoMA demonstrated protective effects in vivo against LPS-induced acute lung injury.
Conclusions:
- MPoMA is a promising compound for mitigating viral infection and preventing lung epithelial cell damage.
- The mechanism involves the degradation of p65, leading to reduced inflammatory cytokine production.
- MPoMA may offer therapeutic benefits for acute lung injury and related conditions.
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