C-reactive protein in gallbladder diseases: diagnostic and therapeutic insights

Abstract

The gallbladder is an important component of the hepatobiliary system whose primary function is to aid in digestion of foodstuffs, excretion of drugs and facilitate removal of waste products from the body. The gall bladder is principally a storage organ for bile, chemically modified salts and acids of cholesterol which are synthesized in the liver and which function as surfactants to solubilize fatty substances of limited aqueous solubility. Any disruption in the amount or activity of bile surfactant can lead to an accumulation of insoluble molecular clumps (e.g., gallstones) that deposit in and obstruct fluid movement within the gallbladder, and which can lead to pathological congestion and tissue damage. The natural host defense response to any event that causes tissue damage is to stimulate inflammation, which non-specifically but aggressively reacts to the stimuli so to remove the cause and repair damaged tissues. The C-reactive protein (CRP) is a primarily hepatically produced serum protein whose blood levels increase within 6-10 h of any tissue-damaging event. The extent with which it increases correlates with the level of tissue damage and associated inflammation. CRP levels are reported to be of value in diagnosing acute cholecystitis severity, in predicting the outcome and prognosis of cancerassociated gallbladder resection, and in helping identify cystic structures during emergency laparoscopic cholecystectomies. As an understanding of distinctive CRP structural isoforms is evolving, its role not only as a biomarker but as regulator of both physiologic and pathophysiologic processes of inflammation may be relevant in the understanding of and treatment approaches for gallbladderassociated disease.

C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms

“…Numerous studies emphasize how the conversion of pCRP to mCRP involves insertion into membrane lipids, especially in association with cholesterol, an interaction that is enhanced if the intra-subunit disulfide bond in the CRP subunit is reduced. When mCRP enters membranes, it triggers strong pro-inflammatory responses that, in consideration of observed anti-cancer effects described in various studies, suggest mCRP has favorable therapeutic activities (21,24,51). Lipid-associated mCRP particles (i.e., in micro vesicles) have been measured in patient serum after the onset of an inflammatory reaction associated with disease (25,51,72,73).…”

“…Numerous reports have now appeared describing the structural and functional distinctiveness of conformational isoforms of CRP ( 5 – 7 , 21 , 24 , 25 ). Current evidence describes at least three isoforms of CRP, 1.)…”

C-Reactive Protein and Cancer—Diagnostic and Therapeutic Insights

“…Systemic CRP exists as a pentameric structure (pCRP) made up of five subunits, each containing calcium dependent bindings sites that interact with exposed phosphocholine ligand (PC) which can be expressed on activated plasma membrane ( 103 ). Exposure of PC groups requires phospholipid remodeling such as occurs with Phospholipase A2 activity or oxidation of acyl chains ( 104 ).…”

How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression

“…With the now recognized appreciation that CRP is a dynamic protein that can undergo a pronounced structural and functional change, and by understanding the conditions that contribute to such change in situ , insights can now also be made into the therapeutic relevance of CRP in health and disease. Notably, pCRP will change into mCRP by interacting with activated membranes ( 83 ) using a process that involves an intermediate form of CRP described as mCRP m ( 17 ) or pCRP * ( 63 ). The intermediate structure represents initial stages of subunit dissociation in which the still pentameric protein begins expressing antigenic and functional attributes now known to be characteristic of mCRP.…”

“…By influencing or controlling the conversion of pCRP to mCRP, it may be possible to therapeutically control the rate and extent of anti- and pro-inflammatory responses. Indeed, Caprio et al ( 2 ), have discussed using inhibitors of Phospholipase A 2 (PLA 2 ) to mitigate the production of lyso-PC which is a critical step in binding pCRP and bringing it into juxtaposition to the apolar membrane zone ( 83 ). Pepys et al ( 86 ) designed a small molecule bi-valent compound having phosphocholine groups on opposite ends of a linking group.…”