tretinoin and Sepsis

Sepsis is among the most dangerous known diseases, resulting from the dysregulation of the innate immune system in a process that is characterized largely by proinflammatory cytokines. It manifests as an excessive immune response to a pathogen and often leads to life-threatening complications such as shock and multiple-organ failure. Within the past several decades, much progress has been made to better understand the pathophysiology of sepsis and improve treatment. However, the average case-fatality rate for sepsis remains high. Current anti-inflammatory therapeutics for sepsis are not effective for use as first-line treatments. Focusing on all-

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Lipopolysaccharides; Mice; Sepsis; Tretinoin; Tumor Necrosis Factor-alpha

Pediatric acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia of childhood. But it may have many early complications, especially in developing countries. This study aims to describe the outcome and complications of pediatric APL patients in Bangladesh. This prospective observational study was conducted in the pediatric hematology and oncology department of Bangabandhu Sheikh Mujib Medical University, Dhaka from September 2017 to March 2019. In this study, PML:RAR-α (Promyelocytic leukemia-retinoic acid receptor-α) positive APL cases were included and observed while being treated with risk-directed ATRA (All-trans-retinoic acid) based chemotherapy. Among twenty PML:RAR-α positive APL cases, 13 children were in the high risk group and hemorrhagic manifestations were present in 95% of patients. Post-induction remission was achieved in 85% of the patients. 3-year overall survival was 70% (45-85% with 95% confidence interval). There was no refractory disease or relapses. Neutropenic sepsis was the most common complication and also the most common cause of mortality. In Bangladesh, the 3-year overall survival of pediatric APL is 70% (45-85% with 95% CI). Post-chemotherapy neutropenic sepsis is the most common complication and also the most common cause of mortality in this potentially curable malignancy in Bangladesh.

Topics: Bangladesh; Child; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Sepsis; Tretinoin

Patients are susceptible to immunosuppression in late-stage of sepsis, in which myeloid-derived suppressor cells (MDSCs) is an important contributor. This study aims to investigate whether all-trans-retinoic acid (ATRA), which has been proved to inhibit MDSCs generation in cancer, will ameliorate sepsis-induced immuno-suppression through modulating MDSCs.. A clinically relevant "two-hit'' model of sepsis, the cecal ligation and puncture (CLP) model and secondary pneumonia model, were established in mice. The effects of ATRA on the mortality, the bacterial burden, the expansion and activity of CLP-induced MDSCs, as well as the function of CD4+ T cells were evaluated.. In CLP model, ATRA was found to reduce frequency of MDSCs in spleen of mice and inhibit activity of MDSCs by regulating the generation and activity of arginase-1 and iNOS, and the secretion of immune-supressive cytokines. ATRA administration eventually reduced mortality of secondary infection by Legionella pneumophila in CLP-surviving mice, which might be associated with the restoration of CD4+ T cells proliferating and secreting activity.. ATRA can restore CD4+ T cells dysfunction in sepsis by modulating the expansion and function of MDSCs and therefore provides a potential therapy that targets the immunosuppressive state of sepsis.

Topics: Animals; Arginase; CD4-Positive T-Lymphocytes; Cytokines; Legionella pneumophila; Legionnaires' Disease; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Nitric Oxide Synthase Type II; Sepsis; Tretinoin

The present study was to investigate the effects of rosmarinic acid (RA) in cultured RAW264.7 cells and experimental model of sepsis induced by cecal ligation and puncture in rats and the potential mechanism. Results showed that RA concentration dependently down-regulated the levels of TNF-alpha, IL-6, and high-mobility group box 1 protein in LPS-induced RAW264.7 cells, inhibited the IkappaB kinase pathway, and modulated nuclear factor-kappaB. Intravenous injection of RA alone or in combination with imipenem reduced cecal ligation and puncture-induced lethality in rats. In addition, serum levels of TNF-alpha, IL-6, high-mobility group box 1 protein, triggering receptor expressed on myeloid cells, and endotoxin were down-regulated; in contrast, serum level of IL-10 was up-regulated. Amelioration of hemodynamics and decrease in serum enzyme activities and myeloperoxidase in lung, liver, and small intestine were also observed after RA injection. These data indicate that the antisepsis effect of RA was mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. This article provides the first evidence that RA has the capacity to inactivate inflammatory response in sepsis. The anti-inflammatory mechanism of RA may inhibit activation of the nuclear factor- kappaB pathway by inhibiting IkappaB kinase activity.

Topics: Animals; Anti-Bacterial Agents; Cinnamates; Depsides; Disease Models, Animal; Endotoxins; Gene Expression Regulation; Hemodynamics; Humans; Imipenem; Inflammation; Male; Mice; Myeloid Cells; Rats; Rats, Sprague-Dawley; Rosmarinic Acid; Sepsis; Tretinoin

Coagulation patterns of 19 newly-diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin-ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all-trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Sepsis; Tretinoin