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CQMUH-011 mitigated LPS-induced acute lung injury in neonatal rabbits

ABSTRACT: Background: Neonatal sepsis-associated acute lung injury (ALI) is a therapeutic challenge. This study evaluated the efficacy of CQMUH-011, a novel small-molecule compound, against lipopolysaccharide (LPS)-induced ALI in neonatal rabbits. Methods: Neonatal rabbits at postnatal age 5-7 days were intraperitoneally injected with LPS (50 mg/kg) to induce ALI, and subsequently treated with CQMUH-011 at 675 μg/kg at 0.5 hour. Outcomes within 10-hour of observation were assessed through survival analysis, neurobehavioral assessment, blood gas, histopathological scoring, alveolar phospholipid quantification in bronchoalveolar lavage fluid, RT-PCR for inflammatory mediators and surfactant proteins, and gene expression profiles through transcriptomic analysis. Results: LPS administration induced severe ALI characterized by metabolic acidosis, hypoxemia, lung inflammatory injury, neuromotor dysfunction, and mortality. CQMUH-011 improved neurological deficits, restored blood gas balance, enriched phospholipid pool, reduced lung injury scores, diminished leukocyte infiltration and improved alveolar expansion. RT-PCR results showed significantly mitigated mRNA expressions of proinflammatory cytokines and enhanced surfactant proteins and phospholipid synthesis-associated enzymes. Transcriptomic analysis revealed the dual mechanism of CQMUH-011 by downregulating multiple inflammatory pathways, including cytokine-cytokine receptor interaction, T-helper 17 cell differentiation, interleukin-17 and nuclear transcription factor-kappa B, tumor necrosis factor-α, concurrent with activation of phosphatidylinositol 3-kinase/protein kinase B-dependent cytoprotection, cytoskeletal remodeling, and intercellular junction reinforcement. Conclusions: CQMUH-011 exerts potent anti-inflammatory and lung-protective effects in neonatal ALI by modulating critical inflammatory and repair pathways, making it a promising therapeutic candidate for sepsis-associated ALI.

ORGANISM(S): Oryctolagus cuniculus

PROVIDER: GSE312949 | GEO | 2026/06/18

REPOSITORIES: GEO

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

Project description:Multipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases. Recent studies have demonstrated the ability of MSCs to attenuate inflammation in rodent models of acute lung injury (ALI) suggesting that MSCs may also be beneficial in treating ALI. To better understand how human MSCs (hMSCs) may act in ALI, the lungs of immunocompetent mice were exposed to lipopolysaccharide (LPS) and 4 hr later bone marrow derived hMSCS were delivered by oropharyngeal aspiration (OA). Administration of hMSCs significantly reduced the expression of pro-inflammatory cytokines, neutrophil counts and total protein in bronchoalveolar lavage. There was a concomitant reduction in pulmonary edema as indicated by a decrease in lung wet/dry weight ratio. The anti-inflammatory effects of hMSCs were not dependent on localization to the lung, as intraperitoneal administration of hMSCs also attenuated LPS-induced inflammation in the lung. Microarray analysis revealed significant induction of TNF-α-induced protein 6 (TSG-6) expression by hMSCs 12 hr after OA delivery to LPS-exposed lungs. Knockdown of TSG-6 expression in hMSCs by RNA interference abrogated most of their anti-inflammatory effects. In addition, intra-pulmonary delivery of recombinant human TSG-6 reduced LPS-induced inflammation in the lung. These results show that hMSCs recapitulate the observed beneficial effects of rodent MSCs in animal models of ALI and suggest that the anti-inflammatory properties of hMSCs in the lung are explained, at least in part, by activation of hMSCs to secrete TSG-6. Eight- to 10-week-old female BALB/C mice were treated with either 1 mg/kg lipopolysaccharide (LPS) in 100 μl PBS or an equal volume of PBS, as vehicle control, by oropharyngeal aspiration (OA). Four hours after LPS exposure, 250,000 human multipotent stromal cells in 100 μl of PBS were given by OA and 30 min later a second dose of equal concentration was administered, for a total of 500,000 hMSC. As a control, 200 μl PBS was delivered as described above. After 12 h, total RNA was isolated from (A) lungs of LPS-exposed mice treated with either hMSCs (LPS+MSC) or PBS (LPS+PBS), and (B) lungs of PBS-exposed mice treated with hMSCs (PBS+MSC). To obtain additional controls, hMSCs were mixed in vitro with either LPS- (LPS+MSC in vitro mix) or PBS-exposed (PBS+MSC in vitro mix) mouse lungs just before RNA isolation. RNA samples containing mouse and human RNA were first analyzed for amount of human RNA based on human GAPDH signal from real-time RT PCR. Samples with similar human RNA content were used for both mouse and human microarrays

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CQMUH-011 mitigated LPS-induced acute lung injury in neonatal rabbits

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