Macrophage migration inhibitory factor within the alveolar spaces induces changes in the heart during late experimental sepsis.
Respiratory dysfunction during sepsis is common. However, although lung function can often be adequately supported, death frequently results from cardiovascular collapse. Despite intense investigation, the mechanism underlying the myocardial dysfunction of sepsis remains unclear. Macrophage migration inhibitory factor (MIF), an important cytokine released in sepsis and the acute respiratory distress syndrome, is a known cardiac depressant. We hypothesized that MIF released from the lung results in myocardial dysfunction during sepsis. In murine models of polymicrobial sepsis, we demonstrate a significant increase in the lungs of total and lavagable MIF between 20 and 30 h post induction of sepsis. At 30 h post sepsis, the lungs released MIF into the pulmonary circulation, increasing the plasma concentration by up to 51% in a single pass. Exogenous MIF, instilled into the lungs, increased alveolar keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-2 (MIP2), and tumor necrosis factor alpha (TNFalpha) at 3 h, and plasma KC and MIP2 at 6 h postinstillation. This was associated with an increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. Because changes in mitogen-activated protein kinase activation can lead to myocardial depression, these data suggest that MIF released from the lungs may be responsible, at least in part, for the cardiac dysfunction seen in the late stages of sepsis.
Lin
Xinchun
X
Department of Surgery, Institute for Medical Research at North Shore-LIJ Health System, Manhasset, New York, NY 11030, USA.
Sakuragi
Tohru
T
Metz
Christine N
CN
Ojamaa
Kaie
K
Skopicki
Hal A
HA
Wang
Ping
P
Al-Abed
Yousef
Y
Miller
Edmund J
EJ
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse