Trappin ovine molecule (TOM), the ovine ortholog of elafin, is an acute phase reactant in the lung.
As large animal models continue to play an important role in translating lung-directed therapeutic strategies from laboratory animals to humans, there is an increasing interest in the analysis of endogenous regulators of inflammation at both a genomic and a therapeutic level. To this end, we have sought to characterize the ovine ortholog of elafin, an important regulator of inflammation in humans. We have isolated both the elafin cDNA and gene, which have a similar structure to other species' orthologs. Interestingly, we have isolated two alleles for ovine elafin, which contain a very high number of transglutamination repeats, thought to be important in binding elafin to the interstitium. The mainly mucosal mRNA distribution for ovine elafin suggests that ovine elafin may, like its human ortholog, have functions in innate immunity. This is supported by analysis of elafin and the related protein secretory leukocyte protease inhibitor (SLPI) in ovine bronchoalveolar fluid in response to locally administered lipopolysaccharide and confirmation of them acting as "alarm" antiproteases. We have also cloned the ovine elafin cDNA into an adenoviral vector and have demonstrated correct processing of the secreted protein as well as biological activity. Overexpression of ovine elafin in a lung-derived epithelial cell line has a protective effect against the enzymes human neutrophil and porcine pancreatic elastase. The identification of the ovine elafin gene and its translated protein are important in developing practical strategies aimed at regulating inflammation in the large mammalian lung.
Brown
Thomas I
TI
Rayne Laboratory, Respiratory Medicine Unit, Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
Mistry
Rohit
R
Collie
D David
DD
Tate
Steven
S
Sallenave
Jean-Michel
JM
D000210:Acute-Phase Reaction; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007438:Introns / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D053481:Secretory Leukocyte Peptidase Inhibitor; D017422:Sequence Analysis, DNA; D034561:Sheep, Domestic / Q000235:genetics; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects
D008070:Lipopolysaccharides; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D010196:Pancreatic Elastase