P53 in lung vascular barrier dysfunction

Barabutis, Nektarios

doi:10.1530/vb-20-0004

Cited by 12 publications

(9 citation statements)

References 9 publications

(10 reference statements)

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“…Thus, pharmacological interventions which induce the intracellular abundance of that protein in the lungs, may deliver novel therapeutic possibilities in human disease. The anticancer and anti-inflammatory agents Hsp90 inhibitors [ 175 ] and GHRH antagonists [ 176 , 177 ] are holding the potential to serve towards that purpose, since they affect P53 levels [ 30 , 178 ].…”

Section: Discussionmentioning

confidence: 99%

P53 in the impaired lungs

Uddin

Barabutis

2020

DNA Repair

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Our laboratory is focused on investigating the supportive role of P53 towards the maintenance of lung homeostasis. Acute lung injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary fibrosis, bronchial asthma, pulmonary arterial hypertension, pneumonia and tuberculosis are respiratory pathologies, associated with dysfunctions of this endothelium defender (P53). Herein we review the evolving role of P53 towards the aforementioned inflammatory disorders, to potentially reveal new therapeutic possibilities in pulmonary disease.

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Section: Discussionmentioning

confidence: 99%

P53 in the impaired lungs

Uddin

Barabutis

2020

DNA Repair

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“…The defensive role of P53 is not only limited to protection against cancers. It also mediates robust anti-inflammatory activities in the vasculature, which in turn result in enhanced endothelial barrier function ( Barabutis, 2020a ). The reciprocal regulation of P53 and NF-kB indicates the importance of the former in maintaining physiological homeostasis and adaptation to different environments ( Liu et al., 2009 ).…”

Section: Introductionmentioning

confidence: 99%

P53 deficiency potentiates LPS-Induced acute lung injury in vivo

Uddin

Akhter

Kubra

et al. 2020

Current Research in Physiology

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Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) represent a significant cause of morbidity and mortality in critically ill hospitalized patients. Emerging evidence suggest that the expression levels of P53 in the lungs are associated with the supportive effects of heat shock protein 90 inhibitors and growth hormone releasing hormone antagonists in the endothelium. In the current study, we employed an in vivo model of intratracheal administration of lipopolysaccharides (LPS)-induced ALI to investigate the role of P53 in counteracting LPS-induced lung inflammatory responses. In wild type mice, LPS induced the expression of IL-1α, IL-1β, and TNFα in the lungs, increased bronchoalveolar lavage fluid protein concentration, and activated cofilin. Remarkably; those responses were more potent in P53 knockout mice, suggesting the crucial role of P53 in orchestrating rigorous endothelial defenses against inflammatory stimuli. The present study supports previous endeavors on the protective role of P53 against lung inflammatory disease, and enrich our knowledge on the development of medical countermeasures against ARDS.

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“…P53 functions as an orchestrator of anti-inflammatory signaling. It suppresses the redox regulator APE1/Ref1 [22,44,45], inhibits the RhoA/MLC2 pathway [46] and deactivates the actin severing activity of cofilin in endothelial cells [47,48]. P53 is subjected to phosphorylation and subsequent degradation by bacterial toxins such as lipopolysaccharide [49] and lipoteichoic acid [50].…”

Section: Discussionmentioning

confidence: 99%

Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

et al. 2021

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause thousands of deaths every year and are associated with high mortality rates (~40%) due to the lack of efficient therapies. Understanding the molecular mechanisms associated with those diseases will most probably lead to novel therapeutics. In the present study, we investigated the effects of the Hsp90 inhibitor AUY-922 in the major inflammatory pathways of mouse lungs. Mice were treated with LPS (1.6 mg/kg) via intratracheal instillation for 24 h and were then post-treated intraperitoneally with AUY-922 (10 mg/kg). The animals were examined 48 h after AUY-922 injection. LPS activated the TLR4-mediated signaling pathways, which in turn induced the release of different inflammatory cytokines and chemokines. AUY-922 suppressed the LPS-induced inflammation by inhibiting major pro-inflammatory pathways (e.g., JAK2/STAT3, MAPKs), and downregulated the IL-1β, IL-6, MCP-1 and TNFα. The expression levels of the redox regulator APE1/Ref1, as well as the DNA-damage inducible kinases ATM and ATR, were also increased after LPS treatment. Those effects were counteracted by AUY-922. Interestingly, this Hsp90 inhibitor abolished the LPS-induced pIRE1α suppression, a major component of the unfolded protein response. Our study elucidates the molecular pathways involved in the progression of murine inflammation and supports our efforts on the development of new therapeutics against lung inflammatory diseases and sepsis.

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P53 in lung vascular barrier dysfunction

Cited by 12 publications

References 9 publications

P53 in the impaired lungs

P53 in the impaired lungs

P53 deficiency potentiates LPS-Induced acute lung injury in vivo

Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

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