Secretory low-molecular-weight phospholipases A2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of chronic proliferative cholangitis.

Abstract

Intrahepatic calculi is characterized by an intractable course and frequent recurrences, requiring multiple operative interventions. Chronic proliferative cholangitis, an active and long-standing inflammation of the stone-containing bile ducts with the hyperplasia of epithelia and the proliferation of the duct-associated mucus glands, may underlie the complex nature of the disease. In terms of the pathophysiology, interest has been focused on the role of secretory low-molecular-weight phospholipases A2 (sPLA2s) as inflammatory mediators or factors modulating cell functions via their specific sPLA2-receptor, and also on the production and secretion of altered mucin molecules from the inflamed bile ducts. In search of factors involving chronic proliferative cholangitis, the sPLA2 isoforms in the bile such as the pancreatic-type sPLA2 (group IB sPLA2) and the arthritic-type sPLA2 (group IIA sPLA2), were assayed to correlate protein masses of the sPLA2s with alterations in biliary composition. Furthermore, the steady-state messenger RNA (mRNA) levels of the sPLA2s, the membrane-bound sPLA2-receptor, cystic fibrosis transmembrane conductance regulator (CFTR), and mucin core polypeptide (MUC) genes in the bile ducts were assayed by reverse- transcriptase polymerase chain reaction (RT-PCR). Immunoreactive sPLA2-IB and sPLA2-IIA levels were significantly higher in the bile from the stone-containing hepatic ducts (2315 +/- 677 for sPLA2-IB; 281 +/- 42 for sPLA2-IIA ng/dL, mean +/- SEM; n = 20) than in the ductal bile from gallbladder stone patients (609 +/- 92, P <.01; 22 +/- 2, P <.01; n = 24). The increased sPLA2 levels were associated with a concomitant increase in lysophosphatidylcholine, prostaglandin E2 (PGE2), and total mucin concentrations. The affected bile ducts showed an increased mRNA level of sPLA2-IB and sPLA2-IIA compared with the ducts from control subjects, in whom the mRNAs of the sPLA2-receptor and other sPLA2 isoforms, such as groups V and X sPLA2s, were coincidently expressed. Reflecting the increased amounts of total biliary mucins, the affected ducts showed an increase in mRNA levels of CFTR as well as MUC2, MUC3, MUC5AC, MUC5B, and MUC6 compared with the ducts from control subjects. In intrahepatic calculi, an enhanced expression of the sPLA2s and their possible cross-talk via sPLA2-receptor may be of pathophysiological significance for the chronic proliferative cholangitis, in association with the enhanced CFTR expression and the alterations in mucin gene expression in the bile ducts, probably through potentiating arachidonate metabolism with associated biliary alterations favoring growth of preexisting stones and even further progressions.