lactoferrin and Gastrointestinal-Hemorrhage

Nonsteroidal antiinflammatory drugs (NSAIDs), due to their good efficacy in the treatment of pain, inflammation, and fever, are among the most prescribed class of medicines in the world. The main drawback of NSAIDs is that they induce gastric complications such as peptic ulceration and injury to the intestine. Four NSAIDs, indomethacin, diclofenac, aspirin, and ibuprofen were selected to induce gastropathy in mouse models. It was found that the addition of C-terminal half of bovine lactoferrin (C-lobe) reversed the NSAID-induced injuries to the extent of 47-70% whereas the coadministration of C-lobe prevented it significantly. The C-lobe was prepared proteolytically using serine proteases. The binding studies of C-lobe with NSAIDs showed that these compounds bind to C-lobe with affinities ranging from 2.6 to 4.8 x 10(-4) M. The complexes of C-lobe were prepared with the above four NSAIDs. All four complexes were crystallized and their detailed three-dimensional structures were determined using x-ray crystallographic method. The structures showed that all the four NSAID molecules bound to C-lobe at the newly identified ligand binding site in C-lobe that is formed involving two alpha-helices, alpha10 and alpha11. The ligand binding site is separated from the well known iron binding site by the longest and the most stable beta-strand, betaj, in the structure. Similar results were also obtained with the full length lactoferrin molecule. This novel, to our knowledge, binding site in C-lobe of lactoferrin shows a good complementarity for the acidic and lipophilic compounds such as NSAIDs. We believe this indicates that C-lobe of lactoferrin can be exploited for the prevention of NSAID-induced gastropathy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Cattle; Colostrum; Female; Gastrointestinal Hemorrhage; Gastrointestinal Tract; Lactoferrin; Mice; Models, Molecular; Molecular Conformation; Peroxidase; Pregnancy

Recombinant human lactoferrin (RHLF) was tested for its ability to prevent non-steroidal anti-inflammatory drug (NSAID)-induced intestinal injury in rats and mice. Acute and chronic models using indometacin, naproxen and diclofenac were used. Measurements were made of intestinal bleeding and inflammation. Orally administered RHLF was effective at preventing acute NSAID-induced increases in gut bleeding and myeloperoxidase activity. Oral RHLF was also effective at blocking some chronic manifestations of indometacin usage. Protection by RHLF of the intestinal tract from NSAIDs appears to be linked to attenuation of neutrophil migration to the intestine, and is independent of prostaglandins and nitric oxide. RHLF does not bind to the NSAID or interfere with the NSAID biological activity. We conclude that orally administered RHLF is effective at preventing NSAID-induced intestinal injury in rodents and should be investigated for this potential therapeutic use in man.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Gastrointestinal Hemorrhage; Humans; Indomethacin; Lactoferrin; Male; Naproxen; Pain Measurement; Protein Binding; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Topics: Colitis; Escherichia coli Infections; Feces; Gastrointestinal Hemorrhage; Humans; Lactoferrin