Abstract
ObjectiveWe previously demonstrated that promoting Beclin-1–dependent autophagy is cardiac protective during endotoxemia shock, suggesting that autophagy-based approaches may become a promising therapeutic strategy for sepsis. In this study, we applied both genetic and pharmacological approaches to evaluate whether Beclin-1 activation improves sepsis outcomes in a model of pneumonia-induced sepsis.MethodsSepsis was induced in mice by Klebsiella pneumoniae infection via intubation, and outcomes of clinical sickness scores, systemic infection, inflammation, survival, and pulmonary pathology were examined. Evaluation of Beclin-1 activation was achieved by comparing strains of C57BL/6J wild type and Becn1F121A that carries a transgenic expression of Beclin-1–active mutant F121A, and by comparing animal groups treated with Beclin-1–activating peptide, Tat-beclin-1 peptide (TB-peptide), or with vehicle control. The status of autophagy in the lung tissue was examined in autophagy reporter mice, CAG-RFP-EGFP-LC3, by fluorescence microscopy.ResultsPulmonary infection by K. pneumoniae produced an insufficient, maladaptive autophagy in the lung. Activation of Beclin-1 by forced expression of active mutant Becn1F121A or by treatment with TB-peptide enhanced autophagy and significantly reduced sickness scores, systemic infection, and circulating and pulmonary cytokine production. Both approaches demonstrated notable benefits in limiting post-infection pathogenesis in the lung, such as decreases in alveolar congestion, hemorrhage, infiltration of inflammatory cells, and alveolar wall thickness.ConclusionData suggest that targeted activation of Beclin-1 alleviates adverse outcomes of pneumonia-induced sepsis, and thus, possess a therapeutic potential.
Highlights
Sepsis is a life-threatening condition of organ dysfunction caused by a deregulated host response to infection (Singer et al, 2016)
Data suggest that targeted activation of Beclin-1 alleviates adverse outcomes of pneumonia-induced sepsis, and possess a therapeutic potential
We previously demonstrated that sepsis triggers damage in mitochondria, resulting in an overproduction of mitochondria-derived danger-associated molecular patterns (DAMPs), such as mitochondrial reactive oxygen species and fragmented mitochondrial DNA (Zang et al, 2007; Zang et al, 2012a; Zang et al, 2012b)
Summary
Sepsis is a life-threatening condition of organ dysfunction caused by a deregulated host response to infection (Singer et al, 2016). We previously demonstrated that sepsis triggers damage in mitochondria, resulting in an overproduction of mitochondria-derived danger-associated molecular patterns (DAMPs), such as mitochondrial reactive oxygen species (mtROS) and fragmented mitochondrial DNA (mtDNA) (Zang et al, 2007; Zang et al, 2012a; Zang et al, 2012b). These harmful molecules exacerbate myocardial inflammation and cardiac dysfunction during sepsis (Zang et al, 2012b; Yao et al, 2015). This study leads us to postulate that the targeted activation of autophagy factors may become an effective approach to boost adaptive autophagic responses, and improves outcomes in sepsis
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