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Dynamic Network Analysis (DyNA) and Dynamic Hypergraphs (DyHyp) were used to define protein-level inflammatory networks at the local (wound effluent) and systemic circulation (serum) levels from 140 active-duty, injured service members (59 with TBI and 81 non-TBI). Interleukin (IL)-17A was the only biomarker elevated significantly in both serum and effluent in TBI vs. non-TBI casualties, and the mediator with the most DyNA connections in TBI wounds. DyNA combining serum and effluent data to define cross-compartment correlations suggested that IL-17A bridges local and systemic circulation at late time points. DyHyp suggested that systemic IL-17A upregulation in TBI patients was associated with tumor necrosis factor-α, while IL-17A downregulation in non-TBI patients was associated with interferon-γ. Correlation analysis suggested differential upregulation of pathogenic Th17 cells, non-pathogenic Th17 cells, and memory/effector T cells. This was associated with reduced procalcitonin in both effluent and serum of TBI patients, in support of an antibacterial effect of Th17 cells in TBI patients. Dysregulation of Th17 responses following TBI may drive cross-compartment inflammation following combat injury, counteracting wound infection at the cost of elevated systemic inflammation.

Background Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. Methods 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. Discussion MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. Trial Registration: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

The absence of early outcome biomarkers for pediatric acute liver failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome subgroups. Serum samples from 101 participants in the PALF study, collected over the first 7 d following enrollment, were assayed for 27 inflammatory mediators. Outcomes (spontaneous survivors [S, n = 61], nonsurvivors [NS, n = 12] and liver transplant patients [LTx, n = 28]) were assessed at 21 d post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian network inference identified a common network motif, with HMGB1 as a central node in all patient subgroups. The networks in S and LTx were similar, and differed from NS. Dynamic network analysis suggested similar dynamic connectivity in S and LTx, but a more highly interconnected network in NS that increased with time. A dynamic robustness index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient subgroups. Our results suggest that increasing inflammatory network connectivity is associated with nonsurvival in PALF and could ultimately lead to better patient outcome stratification.

Improper compartmentalization of the inflammatory response leads to systemic inflammation in sepsis. Hemoadsorption (HA) is an emerging approach to modulate sepsis-induced inflammation. We sought to define the effects of HA on inflammatory compartmentalization in Escherichia coli-induced fibrin peritonitis in rats.HA both reprograms and recompartmentalizes inflammation in sepsis. Sprague Dawley male rats were subjected to E. coli peritonitis and, after 24 h, were randomized to HA or sham treatment (sepsis alone). Venous blood samples collected at 0, 1, 3 and 6 h (that is, 24-30 h of total experimental sepsis), and peritoneal samples collected at 0 and 6 h, were assayed for 14 cytokines along with NO(2)(-/)NO(3)(-). Bacterial counts were assessed in the peritoneal fluid at 0 and 6 h. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, CXCL-1, and CCL2 were significantly reduced in HA versus sham. Principal component analysis (PCA) suggested that inflammation in sham was driven by IL-6 and TNF-α, whereas HA-associated inflammation was driven primarily by TNF-α, CXCL-1, IL-10 and CCL2. Whereas -peritoneal bacterial counts, plasma aspartate transaminase levels and peritoneal IL-5, IL-6, IL-18, interferon (IFN)-γ and NO(2)(-)/NO(3)(-) were significantly lower, both CXCL-1 and CCL2 as well as the peritoneal-to-plasma ratios of TNF-α, CXCL-1 and CCL2 were significantly higher in HA versus sham, suggesting that HA-induced inflammatory recompartmentalization leads to the different inflammatory drivers discerned in part by PCA. In conclusion, this study demonstrates the utility of combined in vivo/in silico methods and suggests that HA exerts differential effects on mediator gradients between local and systemic compartments that ultimately benefit the host.

Nitric oxide (NO) is a colorless gas at room temperature and one of the simplest molecules known, yet it has been implicated in a wide variety of regulatory mechanisms ranging from vasodilatation and blood pressure control to neurotransmission. It is also involved in nonspecific immunity and participates in the complex mechanism of tissue injury as a major mediator of inflammatory processes and apoptosis (1). This work focuses on the complex role of NO produced by the inducible form of nitric oxide synthase (iNOS) in inflammatory and autoimmune diseases. Although the earliest studies in the field suggested that NO is a strictly pro-inflammatory macrophage product, it is clear from the current literature that, in fact, NO is made by numerous cell types and is often anti-inflammatory. Much of this dichotomy can be explained by the particular responses of given cells involved in the inflammatory response, but another variable involves the complex chemistry in which NO can participate. As we outline below, various facets of the immune response can be examined from these perspectives.