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Title: Tumor necrosis factor-alpha and acute phase proteins in early pregnant ewes after challenge with peptidoglycan-polysaccharide (PG-PS).

item DOW, T - West Virginia University
item ROGERS-NIEMAN, G - West Virginia University
item HOLASKOVA, I - West Virginia University
item Elsasser, Theodore
item DAILEY, R - West Virginia University

Submitted to: Domestic Animal Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/23/2010
Publication Date: 8/1/2010
Citation: Dow, T.L., Rogers-Nieman, G., Holaskova, I., Elsasser, T.H., Dailey, R.A. 2010. Tumor necrosis factor-alpha and acute phase proteins in early pregnant ewes after challenge with peptidoglycan-polysaccharide (PG-PS). Domestic Animal Endocrinology.39(2):147-154.

Interpretive Summary: Infection of reproductive organs and structures causes millions of dollars in production losses associated with the failure of animals to maintain pregnancies. Many of the infections that affect domestic animals are caused by bacterial organisms that fall into the category of Gram-positive organisms, bacteria that possess the proinflammatory compound peptidoglycal-polysaccharide in their cell walls. The present paper describes a model system that permits the direct testing of the effects of peptidoglycan-polysaccharide on the reproductive process and constitutes the first paper to describe the molecular proinflammatory components that cause the loss of pregnancy. Specifically the paper illustrates that when pregnant sheep are challenged with the peptidoglycal-polysacccharide, the compound elicits a strong release of the cytotoxic hormone tumor necrosis factor-alpha into the systemic circulation. The result of this response is a significant decline in luteinizing hormone and progesterone, the main reproductive hormone needed to maintain pregnancy. Knowing the pathway from infection to tissue destruction and pregnancy loss will facilitate the further identification of intervention and treatment strategies to decreases pregnancy losses due to Gram-positive bacterial infection.

Technical Abstract: Bacterial infection shortly after breeding interferes with establishment and progression of pregnancy. This is particularly relevant in cases of Gram-positive bacterial infection wherein it can be demonstrated that the injection of peptidoglycan-polysaccharide (PG-PS), a component of Gram-positive bacteria into sheep on d 5 of pregnancy, results in embryonic death. Increased embryonic loss could occur as a result of an increase in concentration of pro-inflammatory cytokines and acute phase response (APR) modifiers and proteins. In particular, changes in patterns of tumor necrosis factor-alpha (TNF-a) and down-stream immunoeffectors could be detrimental to early pregnancy. Experiments were designed to evaluate APR response in ewes to injection of PG-PS on d 5 after breeding. Ewes were mated (d 0) and catheters were inserted into the jugular and saphenous veins on d 4. On d 5 ewes were challenged with saline or 30 µg/kg (Exp 1) or 60 µg/kg BW PG-PS (Exp 2). Blood samples were collected every 15 min for 6 h (Exp 1) and every 15 min for 2 h, hourly for 12 h, and at 24, 36, and 48 h (Exp 2). Clinical signs of infection/inflammation (lethargy, loss of appetite and vaginal discharge), in addition to body temperature were monitored in Exp 2. Concentrations of TNF-a, progesterone (P4), SAA and Hp were quantified. Ewes responded to 60 µg/kg BW PG-PS challenge with fever, vaginal discharge, embryonic loss, loss of appetite, and lethargy. After challenge with either 30 µg/kg or 60 µg/kg PG-PS, TNF-a increased in the posterior vena cava. Concentrations of SAA and Hp in jugular increased after challenge with 60 µg/kg. All ewes treated with 60 µg/kg PG-PS either lost pregnancies or functionality of the CL, identified by decreased P4 concentration on d 21. Utilizing logistic regression, pregnancy rate on d 21 was predicted to depend on TNF-a and Hp concentrations on d 5, and P4 concentration on d 14. In conclusion, injection of PG-PS resulted in increased serum concentrations of APR and pro-inflammatory cytokine related to loss of early pregnancy.