Fatty acid nitroalkene reversal of established lung fibrosis

Koudelka, Adolf; Cechova, Veronika; Rojas, Mauricio; Mitash, Nilay; Bondonese, Anna; Croix, Claudette St.; Ross, Mark A.; Freeman, Bruce Α.

doi:10.1016/j.redox.2021.102226

Cited by 13 publications

(9 citation statements)

References 151 publications

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“…In terms of identification of novel agents for IPF treatment, a small molecule electrophilic nitroalkene, nitro-oleic acid (NO2-OA), reversed key indices of fibrosis in mice PCLS prepared 14 days post-bleomycin ( Koudelka et al, 2022 ). Positive findings showed reductions in COL1A1 and FN1 gene expression, and other markers of myofibroblast differentiation, proliferation and collagen deposition.…”

Section: Investigations Of Airway Reactivity and Fibrosis In Pclsmentioning

confidence: 99%

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

et al. 2023

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Precision cut lung slices (PCLS) have emerged as powerful experimental tools for respiratory research. Pioneering studies using mouse PCLS to visualize intrapulmonary airway contractility have been extended to pulmonary arteries and for assessment of novel bronchodilators and vasodilators as therapeutics. Additional disease-relevant outcomes, including inflammatory, fibrotic, and regenerative responses, are now routinely measured in PCLS from multiple species, including humans. This review provides an overview of established and innovative uses of PCLS as an intermediary between cellular and organ-based studies and focuses on opportunities to increase their application to investigate mechanisms and therapeutic targets to oppose excessive airway contraction and fibrosis in lung diseases.

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Section: Investigations Of Airway Reactivity and Fibrosis In Pclsmentioning

confidence: 99%

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

et al. 2023

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“…Collagen deposition can also increase elastic stiffness of airways and lung tissue ( Li and Wu, 2018 ; Hough et al, 2020 ; Karna et al, 2020 ). NO 2 -OA treatment also promotes collagen degradation by tissue resident macrophages in murine models of lung fibrosis ( Koudelka et al, 2022 ). We speculate that a possible mechanism by which NO 2 -OA attenuates lung elastance is by the modulation of gut proline metabolism by microbiota and downregulation of lung proline biosynthesis by pyrroline-5-carboxylate reductase 1 (PYCR1), leading to reduced deposition of elastin and collagen in the lungs.…”

Section: Discussionmentioning

confidence: 99%

Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma

et al. 2023

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Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2-OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.

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“…For PCR analysis, cells were scraped into TRIzol (Invitrogen: 15596026). RNA was isolated, concentration measured, and cDNA prepared as described previously (96). FAM-dyed primers (all purchased from Taqman) were used: Gclm (Mm01324400_m1), Ho1 (Mm00516005_m1), Il1b (Mm00434228_m1), Il6 (Mm99999064_m1), Ccl2 (Mm00441242_m1), Nos2 (Mm00440502_m1), Nqo1 (Mm01253561_m1), and VIC-dyed Actin (Mm00607939_s1) was used as endogenous control.…”

Section: Methodsmentioning

confidence: 99%

Lipoxin A₄yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling

Koudelka,

Buchan,

Cechova

et al. 2024

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The enzymatic oxidation of arachidonic acid is proposed to yield trihydroxytetraene species (termed lipoxins) that resolve inflammation via ligand activation of the formyl peptide receptor, FPR2. While cell and murine models activate signaling responses to synthetic lipoxins, primarily 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid (lipoxin A4, LXA4), there are expanding concerns about the biological formation, detection and signaling mechanisms ascribed to LXA4and related di- and tri-hydroxy ω-6 and ω-3 fatty acids. Herein, the generation and actions of LXA4and its primary 15-oxo metabolite were assessed in control, LPS-activated and arachidonic acid supplemented RAW 264.7 macrophages. Despite protein expression of all enzymes required for LXA4synthesis, both LXA4and its 15-oxo-LXA4metabolite were undetectable. Moreover, synthetic LXA4and the membrane permeable 15-oxo-LXA4methyl ester that is rapidly de-esterified to 15-oxo-LXA4, displayed no ligand activity for the putative LXA4receptor FPR2, as opposed to the FPR2 ligand WKYMVm. Alternatively, 15-oxo-LXA4, an electrophilic α,β-unsaturated ketone, alkylates nucleophilic amino acids such as cysteine to modulate redox-sensitive transcriptional regulatory protein and enzyme function. 15-oxo-LXA4activated nuclear factor (erythroid related factor 2)-like 2 (Nrf2)-regulated gene expression of anti-inflammatory and repair genes and inhibited nuclear factor (NF)-κB-regulated pro-inflammatory mediator expression. LXA4did not impact these macrophage anti-inflammatory and repair responses. In summary, these data show an absence of macrophage LXA4formation and receptor-mediated signaling actions. Rather, if LXA4were present in sufficient concentrations, this, and other more abundant mono- and poly-hydroxylated unsaturated fatty acids can be readily oxidized to electrophilic α,β-unsaturated ketone products that modulate the redox-sensitive cysteine proteome via G-protein coupled receptor-independent mechanisms.

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Fatty acid nitroalkene reversal of established lung fibrosis

Cited by 13 publications

References 151 publications

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma

Lipoxin A₄yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling

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Fatty acid nitroalkene reversal of established lung fibrosis

Cited by 13 publications

References 151 publications

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

Perspectives on precision cut lung slices—powerful tools for investigation of mechanisms and therapeutic targets in lung diseases

Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma

Lipoxin A4yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling

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Lipoxin A₄yields an electrophilic 15-oxo metabolite that mediates FPR2 receptor-independent anti-inflammatory signaling