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SUMMARY
Epithelial cells which line mucosal surfaces are the first line of defense against bacterial invasion and infection. Recent studies have also indicated that epithelial cells contribute significantly to the orchestration of ongoing inflammatory processes. The present invention provides that antimicrobial peptides expressed by human epithelial cells, including BPI (an antibacterial and endotoxin-neutralizing molecule previously associated with neutrophils), can be stimulated and its production increased in the presence of the compounds of the invention, discussed vide infra. Moreover, epithelial cells express antimicrobial peptides whose primary function includes killing of invading microorganisms.
This family of unrelated peptides includes peroxidase, lactoferrin, lysozyme, phospholipase A2, secretory leukoprotease inhibitor (SLPI), and defensins (1A).
The present invention is intended to include the use of compounds presented herein for interaction with the peroxidase, lactoferrin, lysozyme, phospholipase A2, secretory leukoprotease inhibitor (SLPI), and defensins (1A) and including BPI.
Moreover, the present invention provides that epithelial antimicrobial peptides, such as BPI, are transcriptionally regulated transcriptionally regulated by analogs of endogenously occurring anti-inflammatory molecules (aspirintriggered lipoxins, ATLa). Initial studies to verify microarray analysis revealed that epithelial cells of wide origin (oral and intestinal mucosa) express BPI and each is similarly regulated by ATLa. Studies aimed at localization of BPI revealed that such expression occurs on the cell surface of cultured epithelial cell
lines and dominantly localizes to epithelia in human mucosal tissue. Functional studies employing a BPI-neutralizing anti-serum revealed that surface BPI blocks endotoxin-mediated signaling in epithelia and kills Salmonella typhinaurium.
These studies identify a previously unappreciated"molecular shield"for protection of mucosal surfaces against Gram-negative bacteria and their endotoxin.
Experiments aimed at identifying new anti-inflammatory molecules on mucosal surfaces revealed that epithelial cells express surface BPI ; the expression of which was regulated by epithelial exposure to stable analogs of aspirin- triggered lipoxins. Epithelial BPI was found to promote bacterial killing and to diminish endotoxin activation of epithelia. These results identify a new pathway by which anti-inflammatory molecules enhance anti-microbial and endotoxin- neutralizing activity through transcriptional activation of BPI, heretofore solely associated with phagocytes.
It has been surprisingly discovered that lipoxins (LX's), i. e. , lipoxin analogs, and aspirin-triggered lipoxins (ATLa's) of the invention, discussed infra, can be utilized for the stimulation and increased secretion of bactericidal permeability increasing protein (BPI) from various tissues, i. e. , mucosal cells, epithelial cells, for combating infection and/or the invasion of bacteria |
