IL-36 receptor deletion aggravates lung injury and mortality in experimental murine sepsis through epithelial
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE240924 | GEO | 2024/01/02
REPOSITORIES: GEO
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Project description:Inflammation resolution is critical for acute lung injury (ALI) recovery. Interleukin (IL)-10 is a potent anti-inflammatory factor. However, its role in ALI resolution remains unclear. We investigated the effects of IL-10 during the ALI resolution process in a murine lipopolysaccharide (LPS)-induced ALI model. Blockade of IL-10 signaling aggravates LPS-induced lung injury, as manifested by elevated pro-inflammatory factors production and increased neutrophils recruitment to the lung .Thereafter, we used IL-10 GFP reporter mice to discern the source cell of IL-10 during ALI. We found that IL-10 is predominantly generated by B cells during the ALI recovery process. Furthermore, we used IL-10-specific loss in B-cell mice to elucidate the effect of B-cell-derived IL-10 on the ALI resolution process. IL-10-specific loss in B cells leads to increased pro-inflammatory cytokine expression, persistent leukocyte infiltration, and prolonged alveolar barrier damage. Mechanistically, B cell-derived IL-10 inhibits the activation and recruitment of macrophages and downregulates the production of chemokine KC that recruits neutrophils to the lung. Moreover, we found that IL-10 deletion in B cells leads to alterations in the cGMP–PKG signaling pathway. In addition, an exogenous supply of IL-10 promotes recovery from LPS-induced ALI, and IL-10-secreting B cells are present in sepsis-related ARDS. This study highlights that B cell-derived IL-10 is critical for the resolution of LPS-induced ALI and may serve as a potential therapeutic target.
2023-07-19 | GSE236391 | GEO
Project description:Acute lung injury (ALI) is associated with a high mortality rate; however, the underlying molecular mechanisms are poorly understood. The purpose of this study was to investigate the expression profile and related networks of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in lung tissue exosomes obtained from sepsis-induced ALI. A mouse model of sepsis was established using the cecal ligation and puncture method. RNA sequencing was performed using lung tissue exosomes obtained from mice in the sham and CLP groups. Hematoxylin-eosin staining, western blotting, immunofluorescence, quantitative real-time polymerase chain reaction, and nanoparticle tracking analysis were performed to identify relevant phenotypes, and bioinformatic algorithms were used to evaluate competitive endogenous RNA (ceRNA) networks.Thirty lncRNA-miRNA-mRNA interactions were identified, including two upregulated lncRNAs, 30 upregulated miRNAs, and two downregulated miRNAs. Based on the expression levels of DEmRNAs, DELncRNAs, and DEmiRNAs, 30 ceRNA networks were constructed. This study revealed, for the first time, biomarkers of lung tissue exosome RNA and the related networks of lncRNA in sepsis-induced ALI. We revealed a novel molecular mechanism of sepsis-induced ALI, which may support the diagnosis and treatment of sepsis-induced ALI.
2023-12-31 | GSE227365 | GEO
Project description:Acute lung injury (ALI) is associated with a high mortality rate; however, the underlying molecular mechanisms are poorly understood. The purpose of this study was to investigate the expression profile and related networks of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in lung tissue exosomes obtained from sepsis-induced ALI. A mouse model of sepsis was established using the cecal ligation and puncture method. RNA sequencing was performed using lung tissue exosomes obtained from mice in the sham and CLP groups. Hematoxylin-eosin staining, western blotting, immunofluorescence, quantitative real-time polymerase chain reaction, and nanoparticle tracking analysis were performed to identify relevant phenotypes, and bioinformatic algorithms were used to evaluate competitive endogenous RNA (ceRNA) networks.Thirty lncRNA-miRNA-mRNA interactions were identified, including two upregulated lncRNAs, 30 upregulated miRNAs, and two downregulated miRNAs. Based on the expression levels of DEmRNAs, DELncRNAs, and DEmiRNAs, 30 ceRNA networks were constructed. This study revealed, for the first time, biomarkers of lung tissue exosome RNA and the related networks of lncRNA in sepsis-induced ALI. We revealed a novel molecular mechanism of sepsis-induced ALI, which may support the diagnosis and treatment of sepsis-induced ALI.
2023-12-31 | GSE227364 | GEO
Project description:We have previously demonstrated that pre-B-cell colony enhancing factor (PBEF) ais a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility118. In the current study, we explored the mechanistic participation of PBEF in ALI and ventilator-induced associated lung injury (VIALI). Initial in vitro studies and demonstrated rhPBEF aas a direct rat neutrophil chemotactic factor in vitro producing marked in vivo increases in BAL leukocytes (PMNs) in vivo following (intratracheal injection (,IT) in C57B6 mice. These latter changes were accompanied by increased BAL levels of the PMN chemoattractants (, KC and MIP2), and modest changes in lung vascular and but were not associated with significant increasesin alveolar permeability. We next explored the potential synergism between rhPBEF administration (IT) and a mechanical ventilation model of modest VILI lung injury (4 hours, 30 ml/kg tidal volume). We and observed dramatic synergistic increases in BAL PMNs, and both BAL protein and cytokine levels (IL-6, TNF-?, KC). Gene expression profiling Microarray analysis further supported a major role for PBEF in the induction of gene modules associated with ALI and VALI (NFkB pathway, leukocyte extravasation, apoptosis, toll receptor signaling). Finally, we exposed wild type and heterozygous PBEF+/- mice (targeted deletion of a single PBEF allele deletion) to a model of severe VILImechanical ventilation-induced lung injury (4 hours, 40 ml/kg tidal volume). PBEF+/- mice were significantly protected from VIALI-associated increases in BAL protein and BAL IL-6 levels and exhibited significantly reduced expression of ALI-associated gene expression modules. Together, these results indicate that PBEF is a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI. Experiment Overall Design: animals were treated by PBS, rhPBEF (IT administration), VILI (4 hours, 30 ml/kg tidal volume), or both.
2008-06-16 | E-GEOD-9314 | biostudies-arrayexpress
Project description:We have previously demonstrated that pre-B-cell colony enhancing factor (PBEF) ais a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility118. In the current study, we explored the mechanistic participation of PBEF in ALI and ventilator-induced associated lung injury (VIALI). Initial in vitro studies and demonstrated rhPBEF aas a direct rat neutrophil chemotactic factor in vitro producing marked in vivo increases in BAL leukocytes (PMNs) in vivo following (intratracheal injection (,IT) in C57B6 mice. These latter changes were accompanied by increased BAL levels of the PMN chemoattractants (, KC and MIP2), and modest changes in lung vascular and but were not associated with significant increasesin alveolar permeability. We next explored the potential synergism between rhPBEF administration (IT) and a mechanical ventilation model of modest VILI lung injury (4 hours, 30 ml/kg tidal volume). We and observed dramatic synergistic increases in BAL PMNs, and both BAL protein and cytokine levels (IL-6, TNF-?, KC). Gene expression profiling Microarray analysis further supported a major role for PBEF in the induction of gene modules associated with ALI and VALI (NFkB pathway, leukocyte extravasation, apoptosis, toll receptor signaling). Finally, we exposed wild type and heterozygous PBEF+/- mice (targeted deletion of a single PBEF allele deletion) to a model of severe VILImechanical ventilation-induced lung injury (4 hours, 40 ml/kg tidal volume). PBEF+/- mice were significantly protected from VIALI-associated increases in BAL protein and BAL IL-6 levels and exhibited significantly reduced expression of ALI-associated gene expression modules. Together, these results indicate that PBEF is a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Experiment Overall Design: animals were treated by PBS, rhPBEF (IT administration), VILI (4 hours, 30 ml/kg tidal volume), or both.
2008-06-16 | E-GEOD-9368 | biostudies-arrayexpress
Project description:Acute lung injury (ALI) refers to a clinical syndrome characterized by bilateral lung injury, severe lung diffuse failure and hypoxemia caused by non-cardiogenic pulmonary edema.Sepsis is the leading etiology of ALI and a common admission to the intensive care unit, which induces pulmonary inflammation leading disruption of endothelial-epithelial barriers by surge release of pro-inflammatory cytokines that increases the permeability of the alveolar-capillary membrane, pulmonary infiltration, and edema.Ultimately, gas exchange across the alveolar-capillary membrane is severely impaired and acute respiratory failure and hypoxia occur. ALI patients may suffer from pulmonary inflammation and hypoxia simultaneously or sequentially, those two pathophysiological processes may interact mutually and contribute together to the development of ALI. LPS is the most important biological mediator of sepsis induce secretion of inflammatory cytokines including TNF-α, IL-1, and IL-6 from many cell types in response to bacterial toxins. Thus LPS has been commonly used to establish inflammatory ALI models of rats and mice. Clinically, hypoxia commonly coexists with sepsis; however, the role of hypoxia on the development of inflammatory ALI is unclear. The understanding of interaction of hypoxia and inflammation in ALI is of the importance for the treatment of ALI.
2018-08-21 | GSE111241 | GEO
Project description:We have previously demonstrated that pre-B-cell colony enhancing factor (PBEF) ais a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility118. In the current study, we explored the mechanistic participation of PBEF in ALI and ventilator-induced associated lung injury (VIALI). Initial in vitro studies and demonstrated rhPBEF aas a direct rat neutrophil chemotactic factor in vitro producing marked in vivo increases in BAL leukocytes (PMNs) in vivo following (intratracheal injection (,IT) in C57B6 mice. These latter changes were accompanied by increased BAL levels of the PMN chemoattractants (, KC and MIP2), and modest changes in lung vascular and but were not associated with significant increasesin alveolar permeability. We next explored the potential synergism between rhPBEF administration (IT) and a mechanical ventilation model of modest VILI lung injury (4 hours, 30 ml/kg tidal volume). We and observed dramatic synergistic increases in BAL PMNs, and both BAL protein and cytokine levels (IL-6, TNF-?, KC). Gene expression profiling Microarray analysis further supported a major role for PBEF in the induction of gene modules associated with ALI and VALI (NFkB pathway, leukocyte extravasation, apoptosis, toll receptor signaling). Finally, we exposed wild type and heterozygous PBEF+/- mice (targeted deletion of a single PBEF allele deletion) to a model of severe VILImechanical ventilation-induced lung injury (4 hours, 40 ml/kg tidal volume). PBEF+/- mice were significantly protected from VIALI-associated increases in BAL protein and BAL IL-6 levels and exhibited significantly reduced expression of ALI-associated gene expression modules. Together, these results indicate that PBEF is a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Keywords: response to treatment and/or stress
2007-11-01 | GSE9368 | GEO
Project description:We have previously demonstrated that pre-B-cell colony enhancing factor (PBEF) ais a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility118. In the current study, we explored the mechanistic participation of PBEF in ALI and ventilator-induced associated lung injury (VIALI). Initial in vitro studies and demonstrated rhPBEF aas a direct rat neutrophil chemotactic factor in vitro producing marked in vivo increases in BAL leukocytes (PMNs) in vivo following (intratracheal injection (,IT) in C57B6 mice. These latter changes were accompanied by increased BAL levels of the PMN chemoattractants (, KC and MIP2), and modest changes in lung vascular and but were not associated with significant increasesin alveolar permeability. We next explored the potential synergism between rhPBEF administration (IT) and a mechanical ventilation model of modest VILI lung injury (4 hours, 30 ml/kg tidal volume). We and observed dramatic synergistic increases in BAL PMNs, and both BAL protein and cytokine levels (IL-6, TNF-?, KC). Gene expression profiling Microarray analysis further supported a major role for PBEF in the induction of gene modules associated with ALI and VALI (NFkB pathway, leukocyte extravasation, apoptosis, toll receptor signaling). Finally, we exposed wild type and heterozygous PBEF+/- mice (targeted deletion of a single PBEF allele deletion) to a model of severe VILImechanical ventilation-induced lung injury (4 hours, 40 ml/kg tidal volume). PBEF+/- mice were significantly protected from VIALI-associated increases in BAL protein and BAL IL-6 levels and exhibited significantly reduced expression of ALI-associated gene expression modules. Together, these results indicate that PBEF is a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI. Keywords: We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI.
2007-11-01 | GSE9314 | GEO
Project description:Deficiency in IL-36R antagonist caused by loss of function mutations in IL-36RN leads to DITRA (1), a rare inflammatory human disease that belongs to a subgroup of Generalized Pustular Psoriasis (GPP). Herein, we report a novel functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to one observed in DITRA patients which supports and provides new insight in our understanding of IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated IMQ-induced skin pathology at both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic DSS-induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Thus, our results indicate a central role for IL-36 in regulating the pro-inflammatory responses in the skin and epithelial barrier function in the intestine suggesting a new therapeutic potential for IL-36R axis in psoriasis and at the later stages of intestinal pathology.
2020-12-18 | GSE161406 | GEO
Project description:Although respiratory distress is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria; however, no model of malaria-induced lung injury has been definitively established. This work used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of acute lung injury (ALI) in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of cerebral malaria (CM), indicating disruption of the alveolar-capillary membrane barrier – the physiological hallmark of acute lung injury (ALI). In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis comparing malaria-induced ALI with sepsis-induced ALI identified several common gene ontology groups characterizing ALI in these models, including defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. CD36-/- mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM indicate that distinct genetic determinants likely regulate susceptibility to these two important causes of malaria-associated morbidity and mortality. Keywords: Time course
2008-01-31 | GSE9497 | GEO