Markers of collagen synthesis and degradation are increased in serum in severe sepsis: a longitudinal study of 44 patients

Gäddnäs, Fiia; Koskela, Marjo; Koivukangas, Vesa; Risteli, Juha; Oikarinen, Aarne; Laurila, Jouko; Saarnio, Juha; Ala‐Kokko, Tero

doi:10.1186/cc7780

Cited by 39 publications

(53 citation statements)

References 38 publications

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“…Collagen is a well-known marker of liver fibrosis and changes in collagen metabolism have been associated with disease severity in sepsis (Gäddnäs et al, 2009). These findings, together with serology and pathology data ( Figure 1E, F and G) further support a role for doxycycline in limiting liver damage from very early time-points of infection.…”

Section: Doxycycline Improves Liver Pathologymentioning

confidence: 99%

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

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Neves‐Costa

et al. 2019

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Synergy of resistance and disease tolerance mechanisms is necessary for an effectiveimmune response leading to survival and return to homeostasis when an organism is challenged by infection. Antibiotics are used for their resistance enhancement capabilities by decreasing pathogen load, but several classes have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here we report that tetracycline antibiotics, a class of ribosome-targeting drugs, robustly protects against sepsis by inducing disease tolerance, independently from their direct antibiotic properties. Mechanistically, we find that mitochondrial inhibition of protein synthesis perturbs the electron transfer chain and leads to improved damage repair in the lung and fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a partial and acute deletion of CRIF1 in the liver, a critical mitoribosomal component for protein synthesis, we find that mice are protected against bacterial sepsis, an observation which is phenocopied by the transient inhibition of complex I of ETC by phenformin. Together, we demonstrate that ribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a novel mechanism for the induction of disease tolerance.

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Section: Doxycycline Improves Liver Pathologymentioning

confidence: 99%

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

Colaço

Barros

Neves‐Costa

et al. 2019

Preprint

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“…In our model, the plasma concentration of proline was significantly decreased during sepsis compared with healthy controls. One could speculate that, beside the reduced arginine availability, increasing hydroxy lation of proline to hydroxyproline - an essential step to provide collagen for tissue repair, remodeling or wound healing - contributes to the substantially reducedproline plasma concentration during sepsis even in the early phase of the disease [5]. Consequently, targeting arginine deficiency might be essential in patients withsepsis.…”

mentioning

confidence: 99%

Arginine metabolism is markedly impaired in polymicrobial infected mice

et al. 2012

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“…Written informed consent was obtained from 44 patients or their next of kin. Patient demographics have been presented previously [30]. Most of the 44 patients were male (66%) and there were 33 survivors (75%) on day 30 (Table 1).…”

Section: Resultsmentioning

confidence: 95%

“…This investigation is a substudy of an earlier work that examined serum markers of collagen synthesis and degradation in severe sepsis [30]. The inclusion criterion was diagnosis of severe sepsis according to the American College of Chest Physicians/Society of Critical Care Medicine [1].…”

Section: Methodsmentioning

confidence: 99%

Inhibitory effects of serum from sepsis patients on epithelial cell migration in vitro: a case control study

et al. 2017

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BackgroundSepsis delays wound re-epithelialization. In this study we explored the effect of human sepsis sera as well as the effects of cytokines, growth factors and exosomes of sepsis sera treated normal fibroblasts (NF) on keratinocyte migration and proliferation in vitro.MethodsSerum samples were taken on days 1, 4, and 9 from 44 patients diagnosed with severe sepsis, and from 14 matching healthy controls. We evaluated the effects of sepsis serum with or without TNF-α, EGF, EGF receptor inhibitor or exosomes of sepsis sera treated NF on human keratinocyte (HaCaT) proliferation (BrdU assay), viability (MTT assay), and migration (horizontal wound healing model). Cytokine levels of sepsis and healthy sera were measured by multiplex assay. Comparisons between groups were carried out using SPSS statistics and P < 0.05 was considered significant.ResultsSevere-sepsis sera collected on days 1, 4, and 9 reduced keratinocyte proliferation by 6% (P = 0.005), 20% (P = 0.001), and 18% (P = 0.002), respectively, compared to control sera. Cell viability in cultures exposed to sepsis sera from days 4 and 9 was reduced by 38% (P = 0.01) and 58% (P < 0.001), respectively. Open-surface wounds exposed to sepsis sera from days 1 and 4 were larger than those exposed to sera from healthy controls (60 vs. 31%, P = 0.034 and 66 vs. 31%, P = 0.023, respectively). Exosomes of sepsis or healthy sera treated NF inhibited keratinocyte migration. We detected higher serum levels of cytokines TNF-α (5.7 vs. 0.7 pg/ml, P < 0.001), IL-6 (24.8 vs. 3.8 pg/ml, P < 0.001), IL-10 (30.0 vs. 11.9 pg/ml, P = 0.040), and VEGF (177.9 vs. 48.1 pg/ml, P = 0.018) in sepsis sera. Levels of EGF were significantly lower in sepsis sera than in that of healthy controls (6.5 vs. 115.6 pg/ml, P < 0.001). Sepsis serum supplemented with EGF 5 ng/ml and TNF-α in all concentrations improved keratinocyte migration.ConclusionsKeratinocyte viability, proliferation and migration were reduced in severe sepsis in vitro. Exosomes from NF added in healthy or sepsis serum media inhibited keratinocyte migration. Decreased levels of EGF in sepsis sera may partially explain the delay of wound healing with severe-sepsis patients. Increased levels of TNF-α in sepsis sera do not explain diminished keratinocyte migration.

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Markers of collagen synthesis and degradation are increased in serum in severe sepsis: a longitudinal study of 44 patients

Cited by 39 publications

References 38 publications

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

Arginine metabolism is markedly impaired in polymicrobial infected mice

Inhibitory effects of serum from sepsis patients on epithelial cell migration in vitro: a case control study

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