BackgroundComplex biological processes such as acute inflammation induced by trauma/hemorrhagic shock/ (T/HS) are dynamic and multi-dimensional. We utilized multiplexing cytokine analysis coupled with data-driven modeling to gain a systems perspective into T/HS.Methodology/Principal FindingsMice were subjected to surgical cannulation trauma (ST) ± hemorrhagic shock (HS; 25 mmHg), and followed for 1, 2, 3, or 4 h in each case. Serum was assayed for 20 cytokines and NO2 −/NO3 −. These data were analyzed using four data-driven methods (Hierarchical Clustering Analysis [HCA], multivariate analysis [MA], Principal Component Analysis [PCA], and Dynamic Network Analysis [DyNA]). Using HCA, animals subjected to ST vs. ST + HS could be partially segregated based on inflammatory mediator profiles, despite a large overlap. Based on MA, interleukin [IL]-12p40/p70 (IL-12.total), monokine induced by interferon-γ (CXCL-9) [MIG], and IP-10 were the best discriminators between ST and ST/HS. PCA suggested that the inflammatory mediators found in the three main principal components in animals subjected to ST were IL-6, IL-10, and IL-13, while the three principal components in ST + HS included a large number of cytokines including IL-6, IL-10, keratinocyte-derived cytokine (CXCL-1) [KC], and tumor necrosis factor-α [TNF-α]. DyNA suggested that the circulating mediators produced in response to ST were characterized by a high degree of interconnection/complexity at all time points; the response to ST + HS consisted of different central nodes, and exhibited zero network density over the first 2 h with lesser connectivity vs. ST at all time points. DyNA also helped link the conclusions from MA and PCA, in that central nodes consisting of IP-10 and IL-12 were seen in ST, while MIG and IL-6 were central nodes in ST + HS.Conclusions/SignificanceThese studies help elucidate the dynamics of T/HS-induced inflammation, complementing other forms of dynamic mechanistic modeling. These methods should be applicable to the analysis of other complex biological processes.
One VOT defines StO(2) deoxygenation and recovery. That StO(2) and HbT recovery co-vary only in trauma patients suggests that pre-existing vasoconstriction was unmasked by the ischemic challenge consistent with increased sympathetic tone.
This study uses a new strategy to investigate the hypothesis that, of the various Ca2+ channels expressed by a neurosecretory cell, a given channel subtype is coupled more tightly to the exocytotic apparatus than others. The approach is based on the prediction that the degree of inhibition of the secretory response by various Ca2+ channel blockers will differ at low (0.5 mM) and high (5 mM) extracellular Ca2+ concentrations ([Ca2+]o). So, at low [Ca2+]o the K+-evoked catecholamine release from superfused bovine chromaffin cells was depressed 60-70% by 2 microM omega-agatoxin IVA (P/Q-type Ca2+ channel blockade), by 3 microM omega-conotoxin MVIIC (N/P/Q-type Ca2+ channel blockade), or by 3 microM lubeluzole (N/P/Q-type Ca2+ channel blockade); in high [Ca2+]o these blockers inhibited the responses by only 20-35%. At 1-3 microM omega-conotoxin GVIA (N-type Ca2+ channel blockade) or 3 microM furnidipine (L-type Ca2+ channel blockade), secretion was inhibited by 30 and 50%, respectively; such inhibitory effects were similar in low or high [Ca2+]o. Combined furnidipine plus omega-conotoxin MVIIC, omega-agatoxin IVA or omega-conotoxin GVIA exhibited additive blocking effects at both Ca2+ concentrations. The results suggest that Q-type Ca2+ channels are coupled more tightly to exocytotic active sites, as compared to L-type channels. This hypothesis if founded in the fact that external Ca2+ that enters the cell through a Ca2+ channel located near to chromaffin vesicles will saturate the K+ secretory response at both [Ca2+]o, i.e. 0.5 mM and 5 mM. In contrast, Ca2+ ions entering through more distant channels will be sequestered by intracellular buffers and, thus, will not saturate the secretory machinery at lower [Ca2+]o.
BackgroundTrauma/hemorrhagic shock (T/HS) results in cytokine-mediated acute inflammation that is generally considered detrimental.Methodology/Principal FindingsParadoxically, plasma levels of the early inflammatory cytokine TNF-α (but not IL-6, IL-10, or NO2 -/NO3 -) were significantly elevated within 6 h post-admission in 19 human trauma survivors vs. 4 non-survivors. Moreover, plasma TNF-α was inversely correlated with Marshall Score, an index of organ dysfunction, both in the 23 patients taken together and in the survivor cohort. Accordingly, we hypothesized that if an early, robust pro-inflammatory response were to be a marker of an appropriate response to injury, then individuals exhibiting such a response would be predisposed to survive. We tested this hypothesis in swine subjected to various experimental paradigms of T/HS. Twenty-three anesthetized pigs were subjected to T/HS (12 HS-only and 11 HS + Thoracotomy; mean arterial pressure of 30 mmHg for 45–90 min) along with surgery-only controls. Plasma obtained at pre-surgery, baseline post-surgery, beginning of HS, and every 15 min thereafter until 75 min (in the HS only group) or 90 min (in the HS + Thoracotomy group) was assayed for TNF-α, IL-6, IL-10, and NO2 -/NO3 -. Mean post-surgery±HS TNF-α levels were significantly higher in the survivors vs. non-survivors, while non-survivors exhibited no measurable change in TNF-α levels over the same interval.Conclusions/SignificanceContrary to the current dogma, survival in the setting of severe, acute T/HS appears to be associated with an immediate increase in serum TNF-α. It is currently unclear if this response was the cause of this protection, a marker of survival, or both. This abstract won a Young Investigator Travel Award at the SHOCK 2008 meeting in Cologne, Germany.
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