Iron Dysregulation Combined with Aging Prevents Sepsis-Induced Apoptosis1

Javadi, Pardis; Buchman, Timothy G.; Stromberg, Paul E.; Turnbull, Isaiah R.; Vyas, Dinesh; Hotchkiss, Richard S.; Karl, Irene E.; Coopersmith, Craig M.

doi:10.1016/j.jss.2005.03.022

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…First, it examines animals only at a single timepoint. While we chose this timepoint based on multiple studies demonstrating significant differences in the host response to sepsis between young and aged animals 24 hours after CLP (4–6;9;29), the results represent a “snapshot” view and cannot provide any information as to the kinetics of the cytokine levels, microbial burden, or splenic apoptosis. This is especially relevant in light of a recent publication demonstrating that late deaths in experimental sepsis are associated with a different immunopathologic profile than early deaths (30).…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on the immunopathologic response to sepsis

Turnbull

Clark

Stromberg

et al. 2009

Critical Care Medicine

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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: 99%

Effects of aging on the immunopathologic response to sepsis

Turnbull

Clark

Stromberg

et al. 2009

Critical Care Medicine

Self Cite

108

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“…It is by now well established that—while a ‘cytokine storm’ (Huang et al 2005 ; Sriskandan and Altmann 2008 ; Stacey et al 2009 ; Suntharalingam et al 2006 ; Wang and Ma 2008 ; Woo et al 2010 ) is an important part of the aetiology of sepsis/septic shock—these phenomena are associated with the hyperproduction of ROSs (Abdelrahman et al 2005 ; Andrades et al 2005 ; Bulger and Maier 2001 ; Cadenas and Cadenas 2002 ; Closa and Folch-Puy 2004 ; Crimi et al 2006a , b ; Goode and Webster 1993 ; Gutteridge and Mitchell 1999 ; Horn 1998 ; Javadi et al 2005 ; Lagan et al 2008 ; Lemineur et al 2006 ; Mishra 2007 ; Protti and Singer 2006 ; Quinlan et al 2001 ; Redl et al 1993 ; Victor et al 2004 , 2005 ; Vlessis et al 1995 ), and (local and circulating) free iron is raised in sepsis and related conditions (Duvigneau et al 2008 ; Galley et al 1996 , 1997 ; Galley and Webster 1996 ; Ghio et al 2003 ; Lagan et al 2008 ), as is the iron siderophore-binding protein lipocalin-2 (Hattori et al 2009 ).…”

Section: Sepsis Septic Shock and The Systemic Inflammatory Response mentioning

confidence: 99%

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

2010

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Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

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“…Age is a poor prognostic factor for mortality in ICU patients, especially those with sepsis . Elderly people aged 65 years and older comprise approximately 60% of sepsis patients and account for approximately 80% of deaths . With aging worldwide, the number of patients with sepsis has increased, greatly influencing the long‐term prognosis of ICU patients.…”

Section: Introductionmentioning

confidence: 99%

Post‐intensive care syndrome: its pathophysiology, prevention, and future directions

Inoue

Hatakeyama

Kondo

et al. 2019

Acute Medicine & Surgery

376

365

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Expanding elderly populations are a major social challenge in advanced countries worldwide and have led to a rapid increase in the number of elderly patients in intensive care units (ICUs). Innovative advances in medical technology have enabled lifesaving of patients in ICUs, but there remain various problems to improve their long‐term prognoses. Post‐intensive care syndrome (PICS) refers to physical, cognition, and mental impairments that occur during ICU stay, after ICU discharge or hospital discharge, as well as the long‐term prognosis of ICU patients. Its concept also applies to pediatric patients (PICS‐p) and the mental status of their family (PICS‐F). Intensive care unit‐acquired weakness, a syndrome characterized by acute symmetrical limb muscle weakness after ICU admission, belongs to physical impairments in three domains of PICS. Prevention of PICS requires performance of the ABCDEFGH bundle, which incorporates the prevention of delirium, early rehabilitation, family intervention, and follow‐up from the time of ICU admission to the time of discharge. Diary, nutrition, nursing care, and environmental management for healing are also important in the prevention of PICS. This review outlines the pathophysiology, prevention, and future directions of PICS.

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Iron Dysregulation Combined with Aging Prevents Sepsis-Induced Apoptosis1

Cited by 10 publications

References 39 publications

Effects of aging on the immunopathologic response to sepsis

Effects of aging on the immunopathologic response to sepsis

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

Post‐intensive care syndrome: its pathophysiology, prevention, and future directions

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