Lung-derived macrophage migration inhibitory factor in sepsis induces cardio-circulatory depression.
BACKGROUND
Acute lung injury is common during sepsis. Whereas gaseous exchange often can be supported adequately, death results frequently from cardio-circulatory depression, the mechanisms of which remain unclear. The aim of this study was to determine whether cardio-circulatory dysfunction during sepsis results from release of macrophage migration inhibitory factor (MIF) by the lung.


METHODS
Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in adult Sprague-Dawley rats. Macrophage MIF was measured in the plasma sampled from the right ventricle (pre-lung) and left atrium (post-lung).


RESULTS
The concentration of macrophage MIF in each of the post-lung samples was higher than in the corresponding pre-lung sample at 6 h (p = 0.015; paired t-test), 20 h (p = 0.008), and 30 h (p = 0.026) after the induction of sepsis. Next, rats that underwent CLP were treated with either saline (control) or our specific MIF inhibitor, (S, R )-3-(4-hydroxyphenyl)-4,5-dehydro-5-isoxazole acetic acid methyl ester (ISO-1). Echocardiography revealed that ISO-1 significantly improved the left ventricular end-diastolic volume index (p = 0.02), stroke volume index (p = 0.01), and cardiac index (p = 0.02) at 30 h after the induction of sepsis.


CONCLUSIONS
The lung appears to release significant amounts of macrophage MIF into the systemic circulation during late sepsis. Inhibition of MIF in a clinically relevant time frame blocked polymicrobial peritonitis-induced cardio-circulatory dysfunction. Inhibition of MIF may be a useful strategy to prevent cardio-circulatory deterioration associated with late sepsis.
Sakuragi
Tohru
T
Department of Surgery, The Feinstein Institute for Medical Research, 360 Community Drive, Manhasset, NY 11030, USA.
Lin
Xinchun
X
Metz
Christine N
CN
Ojamaa
Kaie
K
Kohn
Nina
N
Al-Abed
Yousef
Y
Miller
Edmund J
EJ
D000818:Animals; D002306:Cardiac Volume; D004195:Disease Models, Animal; D004452:Echocardiography; D007155:Immunologic Factors / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008168:Lung / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000150:complications* / Q000276:immunology; D018805:Sepsis / Q000150:complications* / Q000276:immunology*; D012769:Shock / Q000209:etiology*; D013318:Stroke Volume
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007155:Immunologic Factors; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors