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PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma

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Abstract

Asthma is an inflammatory airway disease wherein bronchoconstriction, airway inflammation, and airway obstruction during asthma attacks are the main problems. It is recognized that imbalance of Th1/Th2 and Th17/Treg is a critical factor in asthma pathogenesis. Manipulation of these with signaling molecules such as mTOR, PI3K, Akt, and MyD88 can control asthma. Mouse model of allergic asthma was produced and treated with ketamine, metformin, metformin and ketamine, triciribine, LY294002, and torin2. MCh challenge test, BALf's Eos Count, the IL-4, 5, INF-γ, eicosanoid, total IgE levels were determined. The MUC5a, Foxp3, RORγt, PI3K, mTOR, Akt, PU.1, and MyD88 gene expressions and histopathology study were done. Asthma groups that were treated with all six components had reduced Penh value, total IgE, IL-4 and IL-5 levels, MUC5a, RORγt, MyD88 and mTOR expression, goblet cell hyperplasia, and mucus hyper-secretion. The eosinophil percentage and Cys-LT level were decreased by metformin and ketamine, triciribine, LY294002, and torin2. The level of IFN-γ was increased in triciribine, LY294002, and torin2. Metformin, metformin and ketamine, triciribine, LY294002, and torin2 reduced Akt and PI3K expression, peribronchial and perivascular inflammation, and increased expression of Foxp3. Torin2 had an effect on PU.1 expression. Inhibition of PI3K/AKT/mTOR and TLR4/MyD88/NF-κB signaling with targeted molecules can attenuate asthma pathology and play an important role in airways protection.

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Abbreviations

AB:

Alcian blue

AHR:

Airway hyperresponsiveness

AKT:

A serine/threonine-specific protein kinase (protein kinase B (PKB))

AMPK:

5-adenosine monophosphate-activated protein kinase

ATF:

Transcription factor

ATP:

Adenosine triphosphate

BALf:

Bronchoalveolar lavage fluid

Cys-LT:

Cysteinyl leukotriene

DC:

Dendritic cell

DNA:

Deoxyribonucleic acid

EOS:

Eosinophil

Foxp3:

Fork head/winged helix

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HDAC:

Histone deacetylase

HDM:

House dust mite

H&E:

Hematoxylin and Eosin

HIF:

Hypoxia-induced factor

HMGB:

High mobility group box

HSF:

Heat shock factor

Flt3L:

fms-like tyrosine 3 kinase ligand

Ig:

Immunoglobulin

IGF:

Insulin-like growth factor

IGF1R:

IGF-1 receptor

IL:

Interleukin

IP:

Intraperitoneal

IT:

Inhalation administration

KLF:

Krüppel-like factor

MCh:

Methacholine

mTOR:

Serine/threonine-protein kinase mammalian target of rapamycin

MyD88:

Myeloid differentiation primary response 88

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

OVA:

Ovalbumin

PAS:

Periodic Acid Schiff

PBS:

Phosphate-buffered saline

PI3K:

Phosphatidylinositol-3-kinase

Qrt:

Quantitative real-time

RORγt:

Nuclear orphan receptor γt

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

T-bet:

T-box expressed in T cells

TGF:

Transforming growth factor

Th:

Lymphocyte T helper

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

Treg:

Lymphocyte T regulatory

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Authors and Affiliations

  1. Department of Thoracic Surgery, Xilingol League Hospital, Xilin Hot City, 026000, Inner Mongolia, China

    Baowei Ma

  2. Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Seyyed Shamsadin Athari

  3. Department of Cardiology, School of Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

    Entezar Mehrabi Nasab

  4. Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, 450003, Henan, China

    Limin Zhao

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  1. Baowei Ma
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Contributions

BM, SSA, EMN, and LZ participated in the design, lab testing, analysis, and drafting of the manuscript. LZ and SSA supervised the study.

Corresponding author

Correspondence to Limin Zhao.

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Animal investigations and studied methods have been approved by the ethical committee of animal house of ix.med.vet.dep, 2021 (No. IX.MED.VET.DEP.REC.2021.290099.0).

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The authors declare no competing interests.

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Ma, B., Athari, S.S., Mehrabi Nasab, E. et al. PI3K/AKT/mTOR and TLR4/MyD88/NF-κB Signaling Inhibitors Attenuate Pathological Mechanisms of Allergic Asthma. Inflammation 44, 1895–1907 (2021). https://doi.org/10.1007/s10753-021-01466-3

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  • DOI: https://doi.org/10.1007/s10753-021-01466-3

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