Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8 -/-mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8 +/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8 -/-macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

Objective Blunt trauma patients may present with similar demographics and injury severity, yet differ with regard to survival. We hypothesized that this divergence was due to different trajectories of systemic inflammation, and utilized computational analyses to define these differences. Design, Setting, and Patients From a cohort of 493 victims of blunt trauma, we conducted a pairwise, retrospective, case-control study of patients who survived over 24h but ultimately died (non-survivors; n=19) and patients who, following ICU admission, went on to be discharged (survivors; n=19). Data on systemic inflammatory mediators assessed within the first 24h and over 7d were analyzed with computational modeling to infer dynamic networks of inflammation. A mouse model of trauma/hemorrhage was used to verify hypotheses derived from the clinical study. Interventions None in patients. Neutralizing anti-IL-17A antibody in mice. Measurements and Main Results Network density among inflammatory mediators in non-survivors increased in parallel with organ dysfunction scores over 7d, suggesting the presence of early, self-sustaining, pathological inflammation involving HMGB1, IL-23, and the Th17 pathway. Survivors demonstrated a pattern commensurate with a self-resolving, predominantly lymphoid response, including higher levels of the reparative cytokine IL-22. Mice subjected to trauma/hemorrhage exhibited reduced organ damage when treated with anti-IL-17A. Conclusions Variable type 17 immune responses are hallmarks of organ damage, survival, and mortality following blunt trauma, and suggest a lymphoid cell-based switch from self-resolving to self-sustaining inflammation.

BackgroundTools to predict death or spontaneous survival are necessary to inform liver transplantation (LTx) decisions in pediatric acute liver failure (PALF), but such tools are not available. Recent data suggest that immune/inflammatory dysregulation occurs in the setting of acute liver failure. We hypothesized that specific, dynamic, and measurable patterns of immune/inflammatory dysregulation will correlate with outcomes in PALF.MethodsWe assayed 26 inflammatory mediators on stored serum samples obtained from a convenience sample of 49 children in the PALF study group (PALFSG) collected within 7 days after enrollment. Outcomes were assessed within 21 days of enrollment consisting of spontaneous survivors, non-survivors, and LTx recipients. Data were subjected to statistical analysis, patient-specific Principal Component Analysis (PCA), and Dynamic Bayesian Network (DBN) inference.FindingsRaw inflammatory mediator levels assessed over time did not distinguish among PALF outcomes. However, DBN analysis did reveal distinct interferon-gamma-related networks that distinguished spontaneous survivors from those who died. The network identified in LTx patients pre-transplant was more like that seen in spontaneous survivors than in those who died, a finding supported by PCA.InterpretationThe application of DBN analysis of inflammatory mediators in this small patient sample appears to differentiate survivors from non-survivors in PALF. Patterns associated with LTx pre-transplant were more like those seen in spontaneous survivors than in those who died. DBN-based analyses might lead to a better prediction of outcome in PALF, and could also have more general utility in other complex diseases with an inflammatory etiology.

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