Sepsis: Something old, something new, and a systems view

Namas, Rami A.; Zamora, Rubén; Namas, Rajaie; An, Gary; Doyle, John C.; Dick, Thomas E.; Jacono, Frank J.; Androulakis, Ioannis P.; Nieman, Gary F.; Chang, Steve; Billiar, Timothy R.; Kellum, John A.; Angus, Derek C.; Vodovotz, Yoram

doi:10.1016/j.jcrc.2011.05.025

Cited by 100 publications

(74 citation statements)

References 148 publications

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“…We and others have carried out combined experimental, clinical, and computational studies with the explicit goal of advancing the understanding of the immune networks involved in trauma/hemorrhage and sepsis at the clinical level (6,10,11,108,144,145,149,151). Over a decade of studies in cells, mice, large animals, and humans, we have developed an integrated view of the postinjury acute inflammatory response, which is regulated by initial chemokine-driven cues and propagated by DAMPs.…”

Section: The Conundrum Of Acute Inflammationmentioning

confidence: 99%

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation

Namas

et al. 2015

Antioxidants & Redox Signaling

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Significance: Traumatic injury elicits a complex, dynamic, multidimensional inflammatory response that is intertwined with complications such as multiple organ dysfunction and nosocomial infection. The complex interplay between inflammation and physiology in critical illness remains a challenge for translational research, including the extrapolation to human disease from animal models. Recent Advances: Over the past decade, we and others have attempted to decipher the biocomplexity of inflammation in these settings of acute illness, using computational models to improve clinical translation. In silico modeling has been suggested as a computationally based framework for integrating data derived from basic biology experiments as well as preclinical and clinical studies. Critical Issues: Extensive studies in cells, mice, and human blunt trauma patients have led us to suggest (i) that while an adequate level of inflammation is required for healing post-trauma, inflammation can be harmful when it becomes self-sustaining via a damage-associated molecular pattern/Toll-like receptor-driven feed-forward circuit; (ii) that chemokines play a central regulatory role in driving either self-resolving or selfmaintaining inflammation that drives the early activation of both classical innate and more recently recognized lymphoid pathways; and (iii) the presence of multiple thresholds and feedback loops, which could significantly affect the propagation of inflammation across multiple body compartments. Future Directions: These insights from data-driven models into the primary drivers and interconnected networks of inflammation have been used to generate mechanistic computational models. Together, these models may be used to gain basic insights as well as serving to help define novel biomarkers and therapeutic targets. Antioxid. Redox Signal. 23, 1370-1387.Trauma: A Significant Burden T rauma/hemorrhagic shock remains the leading cause of death in patients younger than 45 years (70). It is the third leading cause of death worldwide, resulting in five million or 10% of all deaths annually and thus considered the fifth leading cause of significant disability (137). Traumatic injury is a pandemic disease, one that affects every nation in the world regardless of the level of socioeconomic development (70, 71).The disease is acute in onset, but often results in chronic, debilitating health problems that have effects beyond the individual victims. The financial impact of traumatic injuries is staggering: in 2000 in the United States, 10% of hospital discharges were due to injuries, and the direct cost of treating 50 million injury cases was $80.2 billion, with an estimated

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Section: The Conundrum Of Acute Inflammationmentioning

confidence: 99%

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation

Namas

et al. 2015

Antioxidants & Redox Signaling

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“…(14%), and Escherichia coli (13%) (5). Sepsis is a complex and dynamic disease characterized by an exacerbated and systemic immune response to invading pathogens or their related toxins (6,7). This immune response includes pathogen recognition, which triggers the release of inflammatory mediators, such as peptides and proteins, as well as systemic activation of the complement and coagulation cascade (6).…”

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confidence: 99%

Clavanin A Improves Outcome of Complications from Different Bacterial Infections

Silva

Fensterseifer

Rodrigues

et al. 2015

Antimicrob Agents Chemother

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The rapid increase in the incidence of multidrug-resistant infections today has led to enormous interest in antimicrobial peptides (AMPs) as suitable compounds for developing unusual antibiotics. In this study, clavanin A, an antimicrobial peptide previously isolated from the marine tunicate Styela clava, was selected as a purposeful molecule that could be used in controlling infection and further synthesized. Clavanin A was in vitro evaluated against Staphylococcus aureus and Escherichia coli as well as toward L929 mouse fibroblasts and skin primary cells (SPCs). Moreover, this peptide was challenged here in an in vivo wound and sepsis model, and the immune response was also analyzed. Despite displaying clear in vitro antimicrobial activity toward Gram-positive and -negative bacteria, clavanin A showed no cytotoxic activities against mammalian cells, and in acute toxicity tests, no adverse reaction was observed at any of the concentrations. Moreover, clavanin A significantly reduced the S. aureus CFU in an experimental wound model. This peptide also reduced the mortality of mice infected with E. coli and S. aureus by 80% compared with that of control animals (treated with phosphate-buffered saline [PBS]): these data suggest that clavanin A prevents the start of sepsis and thereby reduces mortality. These data suggest that clavanin A is an AMP that could improve the development of novel peptide-based strategies for the treatment of wound and sepsis infections.

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“…epsis is a complex clinical disorder that may culminate in multiorgan failure and death (1,2). Many infectious agents induce a severe inflammatory response by triggering Toll-like receptor (TLR) signaling pathways.…”

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confidence: 99%

Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis

Alazawi

Heath

Waters

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-κB are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-α. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPSinduced lethality in Stat2 −/− mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2 −/− mice. The main determinant of cellular egress in Stat2 −/− mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2 −/− mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-κB target genes by affecting nuclear translocation of NF-κB. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-κB triggered cytokine storm but dependent on cellular egress.

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Sepsis: Something old, something new, and a systems view

Cited by 100 publications

References 148 publications

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation

Insights into the Role of Chemokines, Damage-Associated Molecular Patterns, and Lymphocyte-Derived Mediators from Computational Models of Trauma-Induced Inflammation

Clavanin A Improves Outcome of Complications from Different Bacterial Infections

Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis

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