Infiltration of inflammatory macrophages and neutrophils and widespread pyroptosis in lung drive influenza lethality in nonhuman primates

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(3), P. e1010395 - e1010395

Published: March 10, 2022

Severe influenza kills tens of thousands individuals each year, yet the mechanisms driving lethality in humans are poorly understood. Here we used a unique translational model lethal H5N1 cynomolgus macaques that utilizes inhalation small-particle virus aerosols to define disease. RNA sequencing lung tissue revealed an intense interferon response within two days infection resulted widespread expression interferon-stimulated genes, including inflammatory cytokines and chemokines. Macaques with disease had rapid profound loss alveolar macrophages (AMs) infiltration activated CCR2 + CX3CR1 interstitial (IMs) neutrophils into lungs. Parallel changes AMs bronchoalveolar lavage (BAL) correlated load when compared mild influenza. Both IMs were M1-type which expressed neutrophil chemotactic factors, while genes associated activation generation extracellular traps (NETs). NETs prominent found spaces as well parenchyma. Genes pyroptosis but not apoptosis increased lung, caspases, IL-1β cleaved gasdermin D (GSDMD) present fluid homogenates. Cleaved GSDMD was by epithelial cells large numbers spaces, consistent integrity. colocalized viral NP-expressing alveoli, reflecting infected cells. These novel findings reveal potent cascade neutrophils, elaboration cell death mediates nonhuman primates, extension humans. innate pathways represent promising therapeutic targets prevent severe potentially other primary pneumonias

Language: Английский

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Mesenchymal Stem Cells-Derived Exosomes Alleviate Acute Lung Injury by Inhibiting Alveolar Macrophage Pyroptosis

Stem Cells Translational Medicine, Journal Year: 2024, Volume and Issue: 13(4), P. 371 - 386

Published: Feb. 13, 2024

Abstract Acute lung injury (ALI) is an important pathological process of acute respiratory distress syndrome, yet there are limited therapies for its treatment. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to be effective in suppressing inflammation. However, the effects MSCs-Exo on ALI and underlying mechanisms not well elucidated. Our data showed that MSCs-Exo, but derived from MRC-5 cells (MRC-5-Exo), which human fetal fibroblast cells, significantly improved chest imaging, histological observations, alveolocapillary membrane permeability, reduced inflammatory response mice model. According miRNA sequencing proteomic analysis MRC-5-Exo, may inhibit pyroptosis by miRNAs targeting caspase-1-mediated pathway, proteins with immunoregulation functions. Taken together, our study demonstrated were treating inhibiting alveolar macrophages reducing inflammation response. Its mechanism through pyroptosis-targeting immunoregulating delivered MSCs-Exo. Therefore, a new treatment option early stage ALI.

Language: Английский

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Roles of Macrophages and Endothelial Cells and Their Crosstalk in Acute Lung Injury

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 632 - 632

Published: March 13, 2024

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present life-threatening conditions characterized by inflammation endothelial injury, leading to increased vascular permeability edema. Key players in the pathogenesis resolution of ALI are macrophages (Mφs) cells (ECs). The crosstalk between these two cell types has emerged as a significant focus for potential therapeutic interventions ALI. This review provides brief overview roles Mφs ECs their interplay ALI/ARDS. Moreover, it highlights significance investigating perivascular (PVMs) immunomodulatory (IMECs) crucial participants Mφ–EC crosstalk. sheds light on paves way innovative treatment approaches.

Language: Английский

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Role of pyroptosis in cancer and its therapeutic regulation

European Journal of Pharmacology, Journal Year: 2021, Volume and Issue: 910, P. 174444 - 174444

Published: Aug. 26, 2021

Language: Английский

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Inhibition of the C3a receptor attenuates sepsis-induced acute lung injury by suppressing pyroptosis of the pulmonary vascular endothelial cells

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 184, P. 208 - 217

Published: March 30, 2022

Language: Английский

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Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases

Antioxidants, Journal Year: 2023, Volume and Issue: 12(9), P. 1713 - 1713

Published: Sept. 2, 2023

N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols cystic fibrosis. NAC also administered as an antidote acetaminophen (paracetamol) overdosing. Thanks to wide antioxidative and anti-inflammatory may be benefit other chronic inflammatory fibrotizing respiratory diseases, such obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or silicosis. In addition, exerts low toxicity rare adverse effects even combination with treatments, it cheap easily accessible. This article brings a review information on mechanisms inflammation oxidative stress selected diseases discusses use these disorders.

Language: Английский

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STING-Dependent Sensing of Self-DNA Driving Pyroptosis Contributes to Radiation-Induced Lung Injury

International Journal of Radiation Oncology*Biology*Physics, Journal Year: 2023, Volume and Issue: 117(4), P. 928 - 941

Published: May 24, 2023

Language: Английский

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New insights into Gasdermin D pore formation

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(2), P. 681 - 692

Published: March 18, 2024

Gasdermin D (GSDMD) is a pore-forming protein that perforates the plasma membrane (PM) during pyroptosis, pro-inflammatory form of cell death, to induce unconventional secretion inflammatory cytokines and, ultimately, lysis. GSDMD activated by protease-mediated cleavage its active N-terminal domain from autoinhibitory C-terminal domain. Inflammatory caspase-1, -4/5 are main activators via either canonical or non-canonical pathways inflammasome activation, but under certain stimuli, caspase-8 and other proteases can also activate GSDMD. Activated oligomerize assemble into various nanostructures different sizes shapes perforate cellular membranes, suggesting plasticity in pore formation. Although exact mechanism formation has not yet been deciphered, cysteine residues emerging as crucial modulators oligomerization process. pores thus outcome pyroptosis be modulated regulatory mechanisms. These include availability at PM, control number PM repair mechanisms, modulation lipid environment post-translational modifications. Here, we review latest findings on mechanisms how they tightly regulated for content release fate modulation.

Language: Английский

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Structure-based molecular hybridization design and synthesis of Keap1-Nrf2 inhibitors for anti-inflammatory treatment

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 158, P. 108350 - 108350

Published: March 5, 2025

Language: Английский

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Fragment-Based Discovery of Azocyclic Alkyl Naphthalenesulfonamides as Keap1-Nrf2 Inhibitors for Acute Lung Injury Treatment

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(12), P. 8267 - 8280

Published: May 31, 2023

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor (Nrf2) pathway is a promising strategy to alleviate acute lung injury (ALI). A naphthalensulfonamide NXPZ-2, targeting Keap1-Nrf2 interaction release Nrf2, was confirmed exhibit significant anti-inflammatory activities, however, accompanying nonideal solubility and PK profiles. To further improve properties, twenty-nine novel naphthalenesulfonamide derivatives were designed by fragment-based strategy. Among them, compound 10u with (R)-azetidine group displayed highest PPI inhibitory activity (KD2 = 0.22 μM). The hydrochloric acid form of exhibited 9-fold improvement on water (S 484 μg/mL, pH 7.0) compared NXPZ-2 55 7.0). It could significantly reduce LPS-induced oxidative damages inflammations in vitro vivo. Furthermore, satisfactory pharmacokinetic property revealed. In conclusion, azetidine-containing represents drug candidate for Keap1-targeting ALI treatment.

Language: Английский

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