The Optimal Fluid Strategy Matters in Liver Surgery: A Retrospective Single Centre Analysis of 666 Consecutive Liver Resections.

As optimal intraoperative fluid management in liver surgery has not been established, we retrospectively analyzed our fluid strategy in a high-volume liver surgery center in 666 liver resections. Intraoperative fluid management was divided into very restrictive (<10 m kg-1 h-1) and normal (≥10 mL kg-1 h-1) groups for study group characterization. The primary endpoint was morbidity as assessed by the Clavien-Dindo (CD) score and the comprehensive complication index (CCI). Logistic regression models identified factors most predictive of postoperative morbidity. No association was found between postoperative morbidity and fluid management in the overall study population (p = 0.89). However, the normal fluid management group had shorter postoperative hospital stays (p = <0.001), shorter ICU stays (p = 0.035), and lower in-hospital mortality (p = 0.02). Elevated lactate levels (p < 0.001), duration (p < 0.001), and extent of surgery (p < 0.001) were the most predictive factors for postoperative morbidity. In the subgroup of major/extreme liver resection, very low total (p = 0.028) and normalized fluid balance (p = 0.025) (NFB) were associated with morbidity. Moreover, fluid management was not associated with morbidity in patients with normal lactate levels (<2.5 mmol/L). In conclusion, fluid management in liver surgery is multifaceted and must be applied judiciously as a therapeutic measure. While a restrictive strategy appears attractive, hypovolemia should be avoided.

Intervention of Inflammatory Monocyte Activity Limits Dermal Fibrosis.

Monocytes and monocyte-derived cells are important players in the initiation, progression, and resolution of inflammatory skin reactions. As inflammation is a prerequisite for fibrosis development, we focused on the role of monocytes in cutaneous fibrosis, the clinical hallmark of patients suffering from systemic sclerosis. Investigating the function of monocytes in reactive oxygen species-induced dermal fibrosis, we observed that early monocyte depletion partially reduced disease severity. Low numbers of inflammatory Ly6Chigh monocytes, as well as inhibition of CCR2 and CCL2 in wild type animals by a specific L-RNA aptamer, mitigated disease parameters, indicating a pivotal role for CCR2+ inflammatory monocytes and the CCR2/CCL2 axis in fibrosis development. Of note, mice lacking splenic reservoirs failed to recruit monocytes to the skin and developed less fibrosis. Furthermore, enforced monocyte conversion into noninflammatory, patrolling Ly6Clow monocytes by a nuclear receptor Nur77-agonist also resulted in significantly impaired cutaneous inflammation and dermal fibrosis. Most evident, pronounced monocyte conversion in interferon stimulated gene 12-deficient mice with pronounced nuclear Nur77 signaling completely protected from dermal fibrosis. Our study shows that inflammatory monocytes that are recruited from splenic reservoirs play a key role in the development of skin fibrosis and can be therapeutically challenged by forced conversion via the Nur77/interferon stimulated gene 12 axis.

Production of Extracellular Adenosine by CD73+ Dendritic Cells Is Crucial for Induction of Tolerance in Contact Hypersensitivity Reactions.

Dendritic cells (DCs) express the ecto-5'-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73-derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wild-type (WT) or CD73-deficient (CD73-/-) mice, followed by sensitization and challenge with 2,4-dinitrofluorobenzene. In this model, we show the induction of tolerance by DNTB against 2,4-dinitrofluorobenzene only in WT but not in CD73-/- mice. Analysis of skin DCs showed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrations of extracellular Ado in the lymph node. Moreover, T cells expressed markers for anergy, namely EGR2 and NDRG1 in DNTB-treated WT mice and they exhibited impaired proliferation upon ex vivo re-stimulation. Similarly, in vitro we observed that Ado-producing WT DCs, but not CD73-/- DCs, rendered transgenic T cells from OTII mice (OTII T cells) hyporeactive, decreased their T-cell costimulatory signaling, and induced up-regulation of EGR2 and NDRG1. Thus, these data show that expression of CD73 by DCs, which triggers elevated levels of extracellular Ado, is a crucial mechanism for the induction of anergic T cells and tolerance.