Macrophage Notch1 Participates in LPS-Induced Acute Lung Injury via Regulating CCR5 Expression in Mice

Frontiers in Bioscience-Landmark, Journal Year: 2025, Volume and Issue: 30(4)

Published: April 23, 2025

Background: As pivotal immunoregulatory sentinels in pulmonary defense systems, alveolar macrophages (AMs) play dual roles mediating inflammatory responses and tissue repair processes during various phases of cascades. The present investigation focuses on elucidating the regulatory influence Notch pathway activation within AM populations pathophysiological mechanisms underlying acute lung injury (ALI) development. Methods: To investigate intracellular domain (NICD) C-C chemokine receptor type 5 (CCR5) inflammation, an ALI model was established through lipopolysaccharide (LPS) administration. Complementary studies used macrophage-specific Notch1 knockout mice immortalized bone marrow-derived (iBMDMs). Molecular profiling CCR5 mediators performed real-time quantitative reverse transcription PCR (qRT-PCR) immunofluorescence staining. Functional assessments macrophage migration were carried out using scratch wound healing assays transwell assays. Results: In LPS-induced model, tissues exhibited elevated expression both NICD CCR5. Conversely, attenuated expression, reduced infiltration downregulated pro-inflammatory compared to wild-type controls (p < 0.05). Lung milder Notch1-deficient wild vitro experiments demonstrated that inhibiting CCL5-induced migration. Conclusion: signaling regulates response by modulating induced LPS.

Language: Английский

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Establishment and characterization of an hACE2/hTMPRSS2 knock-in mouse model to study SARS-CoV-2

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 10, 2024

Despite a substantial body of research, we lack fundamental understanding the pathophysiology COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including pulmonary and cardiovascular outcomes, in part due to limitations murine models. Most models use transgenic mice (K18) that express human (h) angiotensin converting enzyme ( ACE2 ), knock-in (KI) mice, or mouse-adapted strains SARS-CoV-2. Further, many SARS-CoV-2 variants produce fatal neurologic disease K18 most studies focus only on first 14 days post inoculation (dpi). To better enable both (&lt;14 dpi) post-acute (&gt;14 infection phases, describe development characterization novel non-lethal KI mouse expresses transmembrane serine protease TMPRSS2 ) genes (h /h ). The were engineered replace orthologous gene loci but remain under control their respective promoters, resulting expression instead counterparts. After intranasal with an omicron strain SARS-CoV-2, h transiently lost weight recovered 7 dpi. Infectious was detected nasopharyngeal swabs 1-2 dpi lung tissues 2-6 dpi, peaking 4 These outcomes similar those inoculated parallel. determine extent which ACE2/ are suitable model physiological assessments measuring locomotion, behavior reflexes, biomonitoring measure cardiac activity respiration, micro computed tomography assess function conducted frequently 6 months inoculation. Male not female showed transient reduction locomotion compared saline treated mice. No significant changes oxygen saturation, heart rate variability, conductivity either sex. When re-inoculated after inoculation, became re-infected signs Together these data show newly generated can be used study mild COVID-19.

Language: Английский

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Synthetic Amphipathic Helical Peptide L-37pA Ameliorates the Development of Acute Respiratory Distress Syndrome (ARDS) and ARDS-Induced Pulmonary Fibrosis in Mice

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8384 - 8384

Published: Aug. 1, 2024

In this study, we evaluated the ability of synthetic amphipathic helical peptide (SAHP), L-37pA, which mediates pathogen recognition and innate immune responses, to treat acute respiratory distress syndrome (ARDS) accompanied by diffuse alveolar damage (DAD) chronic pulmonary fibrosis (PF). For modeling ARDS/DAD, male ICR mice were used. Intrabronchial instillation (IB) 200 µL inflammatory agents was performed an intravenous catheter 20 G into left lung lobe only, leaving right unaffected. Intravenous injections (IVs) dexamethasone (DEX) physiological saline (saline) used as therapies for ARDS/DAD. L37pA inhibited circulating levels cytokines, such IL-8, TNFα, IL1α, IL4, IL5, IL6, IL9 IL10, 75–95%. all cases, computed tomography (CT) data indicate that L-37pA reduced density faster −335 ± 23 Hounsfield units (HU) on day 7 than with DEX saline, −105 29 HU −23 11 HU, respectively. The results functional tests showed treatment 6 h after ARDS/DAD initiation resulted in a more rapid improvement 30–45% functions compared comparison drugs. Our suggest blocked cytokine storm, inflammation, prevented development improved function mouse model. We concluded therapeutic strategy using SAHPs targeting SR-B receptors is potential novel effective inflammation-induced ARDS, DAD various etiologies.

Language: Английский

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Anti-inflammatory effect of nestorone in a lipopolysaccharide-induced acute lung injury model through regulation of the TLR-4/Myd88/NF-κB signaling pathway

Inflammopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Progesterone plays a crucial and indispensable role in regulating immunity attenuating inflammation. Nestorone® (NES, segesterone acetate) is steroidal progestin 19-norprogesterone derivative with no -CH3 group radical at the 6-position. Here, we showed that NES enhanced viability of lipopolysaccharide (LPS)-stimulated THP-1 cell-derived macrophages, potently inhibiting both arms Toll-like receptor 4 (TLR-4) signaling cascade triggered by LPS, especially TLR-4/MyD88/NF-κB pathway. In addition, exerted an anti-inflammatory effect significantly decreasing secretion inflammatory cytokines chemokines type II alveolar epithelial A549 cells macrophages stimulated LPS. Furthermore, evaluated potential pre-treatment, administered 2 h prior to LPS exposure, mitigate acute lung injury induced using LPS-induced (ALI) mouse model. this study, alleviated inflammation damage reducing leukocyte infiltration bronchoalveolar lavage fluid (BALF) tissues mice. Interestingly, our findings indicate dosage 1 mg/kg (91.67%) was more effective than dosages 0.1 (70.83%) or 10 (87.50%), as well dexamethasone (DEX, 5 mg/kg, 83.34%), extending survival mice subjected lethal injury. Additionally, successful alleviating diffuse lungs C57 Our study indicates concentration critical determinant efficacy NES. Consequently, emerges potentially promising therapeutic agent for treatment pulmonary conditions through modulation TLR-4 pathways.

Language: Английский

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COMPARATIVE CHARACTERISTICS OF THE ACCUMULATION OF DIFFERENT VARIANTS OF THE SARS-COV-2 VIRUS (WUHAN, DELTA, OMICRON) IN THE ORGANS OF MODEL ANIMALS

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

ABSTRACT Background The genotypic variability of the SARS-CoV-2 virus has proven to be extremely high, and emergence new strains raises concerns about their possible high virulence, transmissibility, ability bypass responses body’s immune system induced by previous infection or vaccination. Therefore, one main tasks is study pathogenesis various variants using experimental animal biomodels quickly find methods approaches fighting viruses. Methods 60 humanized mice C57BL/6-Tgtn (CAG-human AEC2-IRES-Luciferase-WPRE-polyA) line (hACE2) were used. Mice infected intranasally at different doses with three virus: Wuhan, Delta Omicron. Results We showed that hACE2 mice, when all virus, typical pathological changes in lung consistency comparable those found COVID-19 humans. All developed interstitial pneumonia, characterized inflammatory cell infiltration thickening alveolar septa, characteristic vascular damage. Conclusions At a dose 4 lg plaque-forming unit (PFU), 100% mortality. A dose-dependent effect was established only for Wuhan variants. In comparative assessment mouse model hACE2, it variant leads more severe damage compared

Language: Английский

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