SummaryFibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.

5-Lipoxygenase (5-LOX) plays key roles

The early immune response to microbes is dominated by the recruitment of neutrophils whose primary function is to clear invading pathogens. However, there is emerging evidence that neutrophils play additional effector and regulatory roles. The present study demonstrates that human neutrophils assume antigen cross-presenting functions, and suggests a plausible scenario for the local generation of APC-like neutrophils through the mobilization of unconventional T-cells in response to microbial metabolites. Vγ9/Vδ2 T-cells and MAIT cells are abundant in blood, inflamed tissues and mucosal barriers. Here, both human cell types responded rapidly to neutrophils after phagocytosis of Gram-positive and Gram-negative bacteria producing the corresponding ligands, and in turn mediated the differentiation of neutrophils into APCs for both CD4+ and CD8+ T-cells through secretion of GM-CSF, IFN-γ and TNF-α. In patients with acute sepsis, circulating neutrophils displayed a similar APC-like phenotype and readily processed soluble proteins for cross-presentation of antigenic peptides to CD8+ T-cells, at a time when peripheral Vγ9/Vδ2 T-cells were highly activated. Our findings indicate that unconventional T-cells represent key controllers of neutrophil-driven innate and adaptive responses to a broad range of pathogens.

Advanced haemodynamic monitoring remains a cornerstone in the management of the critically ill. While rates of pulmonary artery catheter use have been declining, there has been an increase in the number of alternatives for monitoring cardiac output as well as greater understanding of the methods and criteria with which to compare devices. The PiCCO (Pulse index Continuous Cardiac Output) device is one such alternative, integrating a wide array of both static and dynamic haemodynamic data through a combination of trans-cardiopulmonary thermodilution and pulse contour analysis. The requirement for intra-arterial and central venous catheterisation limits the use of PiCCO to those with evolving critical illness or at high risk of complex and severe haemodynamic derangement. While the accuracy of trans-cardiopulmonary thermodilution as a measure of cardiac output is well established, several other PiCCO measurements require further validation within the context of their intended clinical use. As with all advanced haemodynamic monitoring systems, efficacy in improving patient-centred outcomes has yet to be conclusively demonstrated. The challenge with PiCCO is in improving the understanding of the many variables that can be measured and integrating those that are clinically relevant and adequately validated with appropriate therapeutic interventions.