Alternatively activated macrophages promote resolution of necrosis following acute liver injury.

BACKGROUND & AIM: Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). METHODS: Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. RESULTS: BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. CONCLUSION: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. LAY SUMMARY: After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

Pilot study evaluating the monitoring of canine diabetes mellitus in primary care practice.

OBJECTIVES: This study aimed to describe how canine diabetes mellitus (CDM) is monitored in primary care practice (PCP) and to report outcomes. DESIGN: Retrospective case review. SETTING: PCP. PARTICIPANTS: 40 dogs of 22 different pedigrees and five crossbreeds. Median age at diagnosis was nine years and six months (eight years six months to 10 years five months). Dogs were diagnosed with CDM between January 1, 2008 and December 30, 2012 and remained with the practice to the study end or until death. PRIMARY AND SECONDARY OUTCOME MEASURES: Stability achievement and death or euthanasia. Consultations for each dog were identified and recorded through records collected from the PCP (January 1, 2008 to December 30, 2012). RESULTS: A median of three consultations per dog occurred in the first month, subsequently falling to a median of one consultation every 19 days thereafter. After the first month postdiagnosis, weight and single blood glucose concentrations were most frequently recorded at 66.8 and 42 per cent of consultations respectively and a blood glucose curve was performed infrequently (17.4 per cent). Serum biochemistry was measured at 8 per cent of consultations and urine culture at only 0.8 per cent. Median survival time (MST) for all dogs was eight months (2-21 months). Eighteen dogs stabilised within three months of diagnosis and their MST was 20.5 months, (10.25-25.75 months), significantly longer than the 22 dogs not achieving stability within three months (MST 2.5 months, 0-5.5 months) (P<0.001). Those dogs not surviving beyond the first month had significantly fewer consultations than those still alive (P<0.005). CONCLUSIONS: This pilot study indicates dogs with CDM managed solely in PCP experience limited monitoring tests and have lower MST than reported in the literature. Recruitment of a larger cohort of CDM cases from a larger number of PCP will help determine whether these results accurately represent this demographic and verify if infrequent testing is associated with a poor outcome. Importantly, prospective evaluation of decision-making around monitoring CDM in PCP is required, to help determine the effectiveness and feasibility of more frequent monitoring strategies, such as those recommended by the American Animal Hospital Association, particularly to influence MST.