AEDL Potential Actions on Inflammation in Lung Cells

AEDL, also referred to as Bronchogen, is a short peptide made of four amino acids that falls into the category of peptide bioregulators. This tetrapeptide is classified amongst the so-called Khavinson’s peptides, which stem from the team of researchers who have most actively studied them.

These short peptides, including AEDL, are thought to work by intracellular mechanisms, which involve reaching the cell’s nucleus and potentially interacting directly with DNA transcription. Specifically, AEDL is investigated in laboratory settings regarding its potential to interact with models of inflammation, particularly in lung cell cultures.

 

Research

AEDL Peptide Potential as a Gene Expression Regulator

Research by Khavinson et al. suggests that AEDL is a short bioregulator that may act on lung cells at the level of transcription.⁽¹⁾ Specifically, it may interact with genes such as NKX2-1, SCGB1A1, SCGB3A2, FOXA1, and FOXA2. The proposed downstream consequences by the authors include reduced inflammatory activity, encouragement of cell differentiation, and resistance to tissue remodeling in laboratory models.

Further research by the same team, this time led by Fedoreyeva et al., suggests that AEDL may bind preferentially to short DNA segments carrying a CNG sequence, where “C” marks cytosine, the “N” stands for any nucleotide (A, T, C or G), and the “G” marks guanine.⁽²⁾ CNG arrangements are of interest because they are common targets for cytosine methylation in eukaryotic cells, and methylation at such sites is generally associated with gene silencing.

If AEDL settles onto these positions, it may interfere with or reshape the methylation process, and thereby possibly interact with which genes to stay active. Research by Morozova et al. looked more closely at how AEDL may interact with specific genes associated with cells’ capacity for cellular renewal via better-supported protein synthesis.⁽³⁾ Specifically, the researchers commented that “The molecular mechanism of the biological peptide activity [may be] related to its ability to epigenetically regulate the synthesis of a wide spectrum of proteins in […] bronchial epithelium”

AEDL Potential Role in Inflammation and Scarring in Laboratory Models

Other researchers such as Titova et al. have also investigated the potential of AEDL for renewal and regeneration, but also reported an apparent anti-inflammatory action of the peptide in bronchial epithelium cells.⁽⁴⁾T he researchers induced cellular damage experimentally, via intermittent exposure to nitrogen oxides.  Exposure to the peptide apparently led to lower accumulation of immune cells such as neutrophils. The researchers also noted an apparent normalization of cell composition and of the pro-inflammatory cytokine and enzyme profile in the cell cultures. Alongside these shifts, the epithelial cells appeared to display signs of structural and functional recovery. Two markers stood out, namely secretory immunoglobulin A (IgA) and surfactant protein B.

IgA is considered to be an indicator of local immunity, while surfactant protein B may help with the management of alveolar surface tension. A related report by Khavinson et al. further researched the potential of AEDL about its anti-inflammatory potential, and suggests that the peptide may also reduce the formation of fibrotic structures after inflammation in lung cell cultures.⁽⁵⁾ Prolonged inflammation may lead to the formation of fibrosis and scarring, which may disrupt the normal function of lung cells such as gas transfer.

Notably, further data from this trial were published by Kuzubova et al., who attempted to investigate how AEDL may hold back tissue remodeling.⁽⁶⁾ According to the publication, the peptide appeared to blunt the hallmark remodeling changes like emphysema-like fibrosis and others, including “goblet cell hyperplasia, squamous metaplasia, lymphocytic infiltration”. The researchers also observed an apparent rise in secretory IgA production, which they considered a sign of normalized epithelial cell function. At the same time, there was an apparent stabilization of cell composition and of the pro-inflammatory cytokine profile in the cell cultures, consistent with reduced neutrophilic inflammation.

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References:

1. Khavinson VK, Popovich IG, Linkova NS, Mironova ES, Ilina AR. Peptide Regulation of Gene Expression: A Systematic Review. Molecules. 2021 Nov 22;26(22):7053. doi: 10.3390/molecules26227053. PMID: 34834146; PMCID: PMC8621050.
2. Fedoreyeva LI, Kireev II, Khavinson VKh, Vanyushin BF. Penetration of short fluorescence-labeled peptides into the nucleus in HeLa cells and in vitro specific interaction of the peptides with deoxyribooligonucleotides and DNA. Biochemistry (Mosc). 2011 Nov;76(11):1210-9. doi: 10.1134/S0006297911110022. PMID: 22117547.
3. Morozova EA, Lin’kova NS, Khavinson VK, Soloviev AY, Kasyanenko NA. In vitro interaction of the AEDL peptide with DNA. J Struct Chem. 2017;58(2):420-424. https://doi.org/10.1134/S0022476617020299
4. Titova ON, Kuzubova NA, Lebedeva ES, Preobrazhenskaya TN, Surkova EA, Dvorakovskaya IV. [Anti-inflammatory and regenerative effect of bronchogen peptide on the bronchial epithelium]. Ross Fiziol Zh Im I M Sechenova. 2017 Feb;103(2):201-8. PMID: 30199201.
5. Khavinson VKh, Linkova NS, Polyakova VO, Kheifets OV, Tarnovskaya SI, Kvetnoy IM. Peptides tissue-specifically stimulate cell differentiation during their aging. Bull Exp Biol Med. 2012 May;153(1):148-51. doi: 10.1007/s10517-012-1664-1. PMID: 22808513.
6. Kuzubova NA, Lebedeva ES, Dvorakovskaya IV, Surkova EA, Platonova IS, Titova ON. Modulating Effect of Peptide Therapy on the Morphofunctional State of Bronchial Epithelium in Rats with Obstructive Lung Pathology. Bull Exp Biol Med. 2015 Sep;159(5):685-8. doi: 10.1007/s10517-015-3047-x. PMID: 26468022.