Mechanical ventilation during experimental sepsis increases deposition of advanced glycation end products and myocardial inflammation.
BACKGROUND
Increasing evidence links advanced glycation end products (AGE) including Nepsilon-(carboxymethyl)lysine (CML) to the development of heart failure. Accumulation of AGE leads to myocardial inflammation, which is considered as one of the possible mechanisms underlying sepsis-induced cardiac dysfunction. We hypothesized that mechanical ventilation (MV) augmented sepsis-induced myocardial CML deposition and inflammation.


METHODS
Sepsis was induced using a modified cecal ligation and perforation (CLP) technique in 36 male adult Sprague Dawley rats. Rats were randomized to four hours of MV with low tidal volume (LTV: 6 ml/kg, PEEP 5 cmH2O, n = 10) or high tidal volume (HTV: 15 ml/kg, PEEP 3 cmH2O, n = 10) 24 hours after the induction of sepsis. Eight rats served as septic, non-ventilated controls and eight as non-septic, non-ventilated controls. After 28 hours all rats were killed. The number of extravascular polymorphonuclear (PMN) leucocytes, macrophages, and lymphocytes was measured as the number of positive cells/mm2. The number of CML positive endothelial cells were semi-quantified based upon an intensity score. The CML intensity score was correlated with the number of inflammatory cells to study the association between CML depositions and inflammation.


RESULTS
Gas exchange was comparable between the ventilated groups. Sepsis induced a significant increase in CML deposition in both ventricles that was significantly augmented by MV compared with non-ventilated septic controls (left ventricle 1.1 +/- 1.0 vs 0.7 +/- 0.1, P = 0.030; right ventricle 2.5 +/- 0.5 vs 0.6 +/- 0.1, P = 0.037), irrespective of ventilatory strategy. In the right ventricle there was a non-significant tendency towards increased CML deposition in the HTV group compared with septic, non-ventilated controls (1.0 +/- 0.1 vs 0.7 +/- 0.09, P = 0.07). Sepsis induced a significant increase in the number of macrophages and PMNs compared with non-ventilated septic controls that was augmented by MV, irrespective of ventilatory strategy. CML deposition was significantly correlated with the number of macrophages and PMNs in the heart.


CONCLUSIONS
Sepsis induces CML deposition in the heart with a predominant right ventricular inflammation that is significantly augmented by MV, irrespective of the ventilatory strategy.
Kneyber
Martin C J
MC
Department of Pediatric Intensive Care, VU university medical center, 1007 MB Amsterdam, The Netherlands. m.c.j.kneyber@bkk.umcg.nl
Gazendam
Roel P
RP
Niessen
Hans W M
HW
Kuiper
Jan-Willem
JW
Dos Santos
Claudia C
CC
Slutsky
Arthur S
AS
Plötz
Frans B
FB
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D018805:Sepsis / Q000150:complications* / Q000628:therapy
D017127:Glycation End Products, Advanced; C048496:N(6)-carboxymethyllysine; D008239:Lysine