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Post-endotoxin exposure-induced lung inflammation and resolution consequences beneficially impacted by lung-delivered IL-10 therapy.

ABSTRACT: Although lung diseases typically result from long-term exposures, even a robust, one-time exposure can result in long-lasting consequences. Endotoxin is a ubiquitous environmental/occupational inflammatory agent often used to model airway inflammation. Using a murine model, the return to lung homeostasis following high dose inhalant lipopolysaccharide (LPS, 10-100 μg) exposure were delineated over 2 weeks. LPS-induced rapid weight loss, release of proinflammatory mediators, and inflammatory cell influx with prolonged persistence of activated macrophages CD11c⁺CD11b⁺ and recruited/transitioning CD11c^intCD11b⁺ monocyte-macrophages out to 2 weeks. Next, lung-delivered recombinant (r) interleukin (IL)-10 was intratracheally administered for 3 doses initiated 5 h following LPS (10 μg) exposure for 2 days. IL-10 therapy reduced LPS-induced weight loss and increased blood glucose levels. Whereas there was no difference in LPS-induced bronchoalveolar lavage airway fluid cellular influx, total lung cell infiltrates were reduced (37%) with rIL-10 treatment. Post-LPS exposure treatment with rIL-10 strikingly reduced lavage fluid and lung homogenate levels of tumor necrosis factor-α (88% and 93% reduction, respectively), IL-6 (98% and 94% reduction), CXCL1 (66% and 75% reduction), and CXCL2 (47% and 67% reduction). LPS-induced recruited monocyte-macrophages (CD11c^intCD11b⁺) were reduced (68%) with rIL-10. Correspondingly, LPS-induced lung tissue CCR2⁺ inflammatory monocyte-macrophage were reduced with rIL-10. There were also reductions in LPS-induced lung neutrophils, lymphocyte subpopulations, collagen content, and vimentin expression. These findings support the importance of studying resolution processes for the development of treatment after unintended environmental/occupational biohazard exposures. Short-term, lung-delivered rIL-10 favorably hastened inflammatory recovery processes following acute, high dose inhalant LPS exposure.

SUBMITTER: Poole JA

PROVIDER: S-EPMC9569365 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Post-endotoxin exposure-induced lung inflammation and resolution consequences beneficially impacted by lung-delivered IL-10 therapy.

Poole Jill A JA Gaurav Rohit R Schwab Aaron A Nelson Amy J AJ Gleason Angela A Romberger Debra J DJ Wyatt Todd A TA

Scientific reports 20221015 1

Although lung diseases typically result from long-term exposures, even a robust, one-time exposure can result in long-lasting consequences. Endotoxin is a ubiquitous environmental/occupational inflammatory agent often used to model airway inflammation. Using a murine model, the return to lung homeostasis following high dose inhalant lipopolysaccharide (LPS, 10-100 μg) exposure were delineated over 2 weeks. LPS-induced rapid weight loss, release of proinflammatory mediators, and inflammatory cell ...[more]

PMID: 36243830

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Project description:Background: Therapeutic options capable of resolving inflammatory lung disease resulting from high-consequence occupational and environmental hazards are lacking. Objective: This study seeks to determine the therapeutic potential of direct lung-delivered interleukin (IL)-10 following repeated high concentration lipopolysaccharide exposures. Methods: C57BL/6 mice were intratracheally instilled with LPS (10μg) and then IL-10 (1μg) or vehicle (saline) control 5-hours later. This LPS exposure and treatment paradigm was then repeated daily for the next 2 days. Serum and lung tissues were collected and assessed for proinflammatory and profibrotic mediators. Lung cell infiltrates were enumerated by flow cytometry. Lung sections were stained for myeloperoxidase (MPO), CCR2, vimentin and post-translational protein citrullination (CIT) and malondialdehyde-acetaldehyde (MAA) modifications. Lung function testing and longitudinal in vivo micro-CT imaging were performed. Whole lungs were profiled using bulk RNA sequencing. Results: Repeated IL-10 therapy significantly (p<0.05) mitigated several LPS-induced adverse effects. IL-10 treatment reduced LPS-induced weight loss and serum pentraxin-2 and IL-6 levels. LPS-induced proinflammatory/profibrotic mediators (i.e., TNF-α, IL-6, CXCL1, CCL2, MMP-8, MMP-9, TIMP-1, fibronectin) were decreased with IL-10 treatment. IL-10 reduced LPS-induced influx of lung neutrophils, CD8+ T cells, NK cells, recruited monocyte-macrophages, and monocytes, as well as tissue expression of CCR2+ monocytes/macrophages, MPO+ neutrophils, vimentin, CIT, and MAA. IL-10 treatment reversed LPS-induced airway hyperresponsiveness. Micro-CT imaging confirmed reduction in LPS-induced lung density by IL-10 treatment. Lung-delivered IL-10 therapy administered after daily repeated endotoxin exposures strikingly reduces lung inflammatory and profibrotic processes and airway dysfunction to hasten lung recovery and resolution. Short-term, lung-localized IL-10 therapy following high-consequence environmental exposure events may represent a novel therapy to prevent chronic lung disease development.

Project description:Background: Interleukin (IL)-26 is a neutrophil-mobilizing and bactericidal cytokine that is enhanced in human airways in vivo in response to endotoxin from Gram-negative bacteria. This cytokine is also enhanced in the airways during exacerbations of chronic obstructive pulmonary disease (COPD). Here, we investigated whether human primary lung fibroblasts (HLF) release IL-26 constitutively and in response to TLR4 stimulation by endotoxin and characterized the effects of bronchodilatory and anti-inflammatory drugs utilized in COPD. Methods: The HLF were stimulated with different concentrations of endotoxin. Cells were also treated with different concentrations of bronchodilatory and anti-inflammatory drugs, with and without endotoxin stimulation. Cytokine protein concentrations were quantified in the cell-free conditioned media [enzyme-linked immunosorbent assay (ELISA)], and the phosphorylation levels of intracellular signaling molecules were determined (phosphoELISA). Results: Whereas HLF displayed constitutive release of IL-26 into the conditioned medium, endotoxin markedly enhanced this release, as well as that of IL-6 and IL-8. This cytokine release was paralleled by increased phosphorylation of the intracellular signaling molecules NF-?B, c-Jun N-terminal kinase (JNK) 1-3, p38, and extracellular signal-regulated kinase (ERK) 1/2. The glucocorticoid hydrocortisone caused substantial inhibition of the endotoxin-induced release of IL-26, IL-6, and IL-8, an effect paralleled by a decrease of the phosphorylation of NF-?B, p38, and ERK1/2. The muscarinic receptor antagonist (MRA) tiotropium, but not aclidinium, caused minor inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-?B. The ?2-adrenoceptor agonist salbutamol caused modest inhibition of the endotoxin-induced release of IL-26 and IL-8, paralleled by a decreased phosphorylation of NF-?B, JNK1-3, and p38. Similar pharmacological effects were observed for the constitutive release of IL-26. Conclusions: The HLF constitute an abundant source of IL-26 that may contribute to local host defense against Gram-negative bacteria. Among the tested drugs, the glucocorticoid displayed the most powerful inhibitory effect, affecting the NF-?B, p38, and ERK1/2 signaling pathways. Whether or not this inhibition of IL-26 contributes to an increased risk for local infections in COPD requires further evaluation.

Dataset Information

Post-endotoxin exposure-induced lung inflammation and resolution consequences beneficially impacted by lung-delivered IL-10 therapy.

Publications

Post-endotoxin exposure-induced lung inflammation and resolution consequences beneficially impacted by lung-delivered IL-10 therapy.

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