Lung-derived macrophage migration inhibitory factor in adult patients with septic shock, and its role in cardiocirculatory depression

Background

Migration inhibitory factor (MIF), a critical proinflammatory mediator in sepsis, has a profound affect on cardiovascular function. Our animal studies show that the lungs release MIF into the systemic circulation during late sepsis. MIF released in this way has direct and immediate access to cardiac cells. The purpose of our study was to assess the lung as a source of MIF in human septic shock patients and to further study the MIF-associated pathways involved in cardiovascular depression.

Materials and methods

Nine adult patients with septic shock in the medical intensive care unit were studied. Blood samples were collected pre-lung (pulmonary artery or central venous catheter) and post-lung (arterial line catheter) at 12, 24 and 48 hours from the time of diagnosis. MIF was measured using an ELISA, and differences in plasma MIF concentration pre-lung versus post-lung were assessed using a paired t test on signed ranks. Furthermore, since inhibition of caspase 3 activity during sepsis reduces myocardial apoptosis and cardiac dysfunction, we examined in vitro the effect of MIF on cardiomyocyte apoptosis.

Results

The mean age of patients was 57.6 years (range 25–82 years). Bloods from six patients were culture positive. There was a wide variation in plasma MIF concentrations in both pre-lung (0.2–64.7 ng/ml) and post-lung (0.2–76.4 ng/ml). However, there was a significant increase in the median MIF level of the post-lung blood (3.9 ng/ml) compared with pre-lung blood samples (2.9 ng/ml, P = 0.005). At 48 hours post diagnosis, eight out of nine individuals had increased MIF concentration post-lung, with a mean increase of 64 ± 49%. These findings were independent of the source or nature of the infection. The basal level of apoptosis in primary cardiomyocytes cultured in defined, serum-free medium was 3.7 ± 0.9% (% TUNEL positive of total nuclei). This increased significantly (P < 0.001) to 15.5 ± 3.9% and 26.0 ± 7.1% when treated with MIF 20 and 30 ng/ml, respectively. Simultaneous treatment of cardiomyocytes with MIF and specific MIF inhibitor ISO1 (50 mM) resulted in significant attenuation of the apoptotic effect, returning apoptosis to a basal level at 4.1 ± 0.6%.

Conclusion

The study demonstrates for the first time in humans that the lung is a major source of MIF in septic shock. The study further suggests that MIF released from the lung may reduce cardiac function by increasing cardiomyocyte apoptosis, and that blocking MIF released from the lung to prevent cardiocirculatory deterioration may provide new strategies for the treatment of sepsis.