NADPH oxidase 1 mediates caerulein-induced pancreatic fibrosis in chronic pancreatitis.

Inflammatory disorders of the pancreas are divided into acute (AP) and chronic (CP) forms. Both states of pancreatitis are a result of pro-inflammatory mediators, including reactive oxygen species (ROS). One of the sources of ROS is NADPH oxidase (Nox). The rodent genome encodes Nox1-4, Duox1 and Duox2. Our purpose was to assess the extent to which Nox enzymes contribute to the pathogenesis of both AP and CP using Nox-deficient mice. Using RT-PCR, Nox1 was found in both isolated mouse pancreatic acini and pancreatic stellate cells (PaSCs). Subsequently, mice with genetically deleted Nox1 were further studied and showed that the histo-morphologic characteristics of caerulein-induced CP, but not caerulein-induced AP, was ameliorated in Nox1 KO mice. We also found that the lack of Nox1 impaired caerulein-induced ROS generation in PaSCs. Using Western blotting, we found that AKT mediates the fibrotic effect of Nox1 in a mouse model of CP. We also found a decrease in phospho-ERK and p38MAPK levels in Nox1 KO mice with CP, but not with AP. Both CP-induced TGF-ß up-regulation and NF-ĸB activation were impaired in pancreas from Nox1 KO mice. Western blotting indicated increases in proteins involved in fibrosis and acinar-to-ductal metaplasia in WT mice with CP. No change in those proteins were observed in Nox1 KO mice. The lack of Nox1 lowered mRNA levels of CP-induced matrix metalloproteinase MMP-9 and E-cadherin repressor Twist in PaSCs. CONCLUSION: Nox1-derived ROS in PaSCs mediate the fibrotic process of CP by activating the downstream redox-sensitive signaling pathways AKT and NF-ĸB, up-regulating MMP-9 and Twist, and producing α-smooth muscle actin and collagen I and III.

Population-based incidence of childhood leukaemias and lymphomas in Spain (1993-2002).

The aim of this study was to estimate the incidence of leukaemias and lymphomas in children according to the International Classification of Childhood Cancer third edition (ICCC-3) in the population covered by the Girona, Valencia, and Zaragoza population-based cancer registries and compare it with the incidence rates in other European countries. All haematological malignancies (HMs) registered between 1993 and 2002 in children below 15 years of age were included in the study. Pathological and haematological diagnoses were reviewed, recoded according to International Classification of Diseases for Oncology-3 and reclassified on the basis of ICCC-3. Sex and age-adjusted incidence rates were calculated, using the world population as standard. Five hundred and seventy-one HMs were registered in the Girona, Valencia and Zaragoza Cancer Registries during the study period. According to ICCC-3, precursor cell leukaemias were the most frequent HMs in children and constituted 60% of all HMs (an age-adjusted incidence rate of 42.7 per million children-years). The second most frequent childhood HM was Hodgkin lymphoma (11.2% of all HMs), yielding an age-adjusted standardized incidence rate of 6.3 per million children-years. With regard to myeloid lineage, acute myeloid leukaemias were the most frequent with a rate of 7.9 per million children-years. The standardized incidence rates for lymphoid leukaemia (1.19) and Burkitt lymphoma (3.94) were statistically higher than the rates observed in Europe. Compared with European data, Spain has a high incidence of lymphoid leukaemias and lymphomas. In particular, a high incidence of Burkitt lymphoma was observed. The causes of this geographical variation are still unknown.