Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium.

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg-1·wk-1), and the second group was injected with 7.5 mg·kg-1·wk-1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

Terminal deoxynucleotidyl transferase-positive cells in spleen, appendix and branchial cleft cysts in pediatric patients.

We evaluated spleens (n = 26), appendices (n = 10) and branchial cleft cysts (n = 6) for TdT-positive cells in pediatric patients. In spleen, appendix and branchial cleft cysts the range of TdT-positivity was 0-13, 0-96 and 0-6 TdT+ cells/hpf, respectively. In spleens, scattered TdT+ cells were seen most frequently in periarteriolar lymphoid sheath regions.

Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor.

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT.

Nodular sarcoidosis of the liver and spleen: analysis of 32 cases.

PURPOSE: To describe the computed tomographic (CT) appearance of nodular hepatosplenic sarcoidosis and its association with stage with chest radiography and clinical status. MATERIALS AND METHODS: Thirty-two patients (21 women, 11 men; aged 25-68 years) with nodular hepatosplenic sarcoidosis were evaluated. CT findings were described along with chest radiographic stage, clinical status, and level of angiotensin-converting enzyme (ACE). RESULTS: Nodules were small, multiple, and of low attenuation. Organomegaly was common. Abdominal adenopathy was present in 76% of the patients. Chest radiographs were normal in 25%; 61% had stage 1 or 2 radiographs. Abdominal or systemic symptoms were present in 66%. ACE level was elevated in 10 (91%) of 11 patients tested. No change in chest radiographic stage was noted in 74% of patients with follow-up radiographs. CONCLUSION: Nodular hepatosplenic sarcoidosis is associated with organomegaly, adenopathy, and symptoms. Nodules were not associated with advanced lung disease and did not herald a change in chest radiographic stage. An elevated ACE level may be helpful in diagnosis.

Changes in the activity of aspartate and alanine aminotransferase caused by aseptic inflammatory reaction and ionizing radiation in the liver, kidney and spleen of mice.

The activity of aspartate aminotransferase and alanine aminotransferase and the content of soluble proteins were determined in mice irradiated with single dose of 100 R or injected with turpentine and in mice subjected to both these stress factors. The aim of this study was determination of changes in the activity of both these enzymes in the liver, kidney and spleen within 48 hours). It was found that the action of both these stress factors caused significant changes in the activity of AspAT and A1AT in the first phase of the response of the organism to stress and caused statistically significant changes of this activity on the second day of the experiment.