Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure

McAuliffe, Priscilla F.; Murday, Michelle; Efron, Philip A.; Scumpia, Philip O.; Ungaro, Ricardo; Abouhamze, Amer; Tannahill, Cynthia L.; Hutchins, Beth; LaFace, Drake; Moldawer, Lyle L.

doi:10.1038/sj.gt.3302600

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…Although we are unaware of any data on IL-10 production in peritoneal fluid following CLP in aged animals, this is consistent with data demonstrating that aging induces elevated splenocyte production of IL-10 following burn injury (22) and local heart and lung mRNA expression of IL-10 in sepsis (6). While tissue-specific IL-10 has been demonstrated to improve survival in young animals in sepsis (23–25), the biological significance of the difference in peritoneal IL-10 in this study is unclear. Multiple possibilities may account for the relative defect in bacterial clearance in aged mice.…”

Section: Discussionmentioning

confidence: 76%

Effects of aging on the immunopathologic response to sepsis

Turnbull

Clark

Stromberg

et al. 2009

Critical Care Medicine

108

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Objective-Aging is associated with increased inflammation following sepsis. The purpose of this study was to determine if this represents a fundamental age-based difference in the host response or is secondary to the increased mortality seen in aged hosts.Design-Prospective, randomized controlled study.Setting-Animal laboratory in a university medical center.Subjects-Young (6-12 week) and aged (20-24 month) FVB/N mice.Interventions-Mice were subjected to 2×25 or 1×30 cecal ligation and puncture (CLP). Measurements and MainResults-Survival was similar in young mice subjected to 2×25 CLP and aged mice subjected to 1×30 CLP (p=0.15). Young mice subjected to 1×30 CLP had improved survival compared to both other groups (p<0.05). When injury was held constant but mortality was greater, both systemic and peritoneal levels of TNF-α, IL-6, IL-10 and MCP-1 were elevated 24 hours after CLP in aged animals compared to young animals (p<0.05). When mortality was similar but injury severity was different, there were no significant differences in systemic cytokines between aged mice and young mice. In contrast, peritoneal levels of TNF-α, IL-6, and IL-10 were higher in aged mice subjected to 1×30 CLP than young mice subjected to 2×25 CLP despite their similar mortalities (p<0.05). There were no significant differences in either bacteremia or peritoneal cultures when animals of different ages sustained similar injuries or had different injuries with similar mortalities.Conclusions-Aged mice are more likely to die from sepsis than young mice when subjected to an equivalent insult, and this is associated with increases in both systemic and local inflammation. There is an exaggerated local but not systemic inflammatory response in aged mice compared to young mice when mortality is similar. This suggests that systemic processes that culminate in death may be age-independent, but the local inflammatory response may be greater with aging.

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Section: Discussionmentioning

confidence: 76%

Effects of aging on the immunopathologic response to sepsis

Turnbull

Clark

Stromberg

et al. 2009

Critical Care Medicine

108

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“…Our group has also shown the protective effect of IL-10 in cultured fetal rat type II epithelial cells exposed to mechanical stretch [6]. In animal models of acute lung injury, administration of IL-10 reduced inflammation [45] and was associated with improved outcome [46]. Recent data also show that inhaled IL-10 reduced pro-inflammatory cytokines and mortality in an adult rat model of ventilator-induced lung injury [47].…”

Section: Discussionmentioning

confidence: 99%

IL‐10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch

Hawwa¹,

Hokenson²,

Wang³

et al. 2011

Pediatric Pulmonology

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“…Furthermore, in a systematic sepsis model in mice, lipoplex-delivered IL-10 significantly prevented lung and other organ injury ( Kabay et al, 2007 ). However, it was reported that adenoviral-delivered IL-10 protected lungs with improved outcome only when a relatively low dose of vector was administered and that survival rates actually worsened at higher doses ( McAuliffe et al, 2006 ). This highlights the inherent problems associated with using a proinflammatory viral vector to treat an inflammatory disease.…”

Section: Gene Delivery Systemsmentioning

confidence: 99%

Gene Therapy for Acute Respiratory Distress Syndrome

Liu

Dean

2022

Front. Physiol.

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Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.

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Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure

Cited by 10 publications

References 36 publications

Effects of aging on the immunopathologic response to sepsis

Effects of aging on the immunopathologic response to sepsis

IL‐10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch

Gene Therapy for Acute Respiratory Distress Syndrome

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