*From the Rayne Laboratory (Drs. Donnelly and Haslett), University of Edinburgh; Picower Institute For Medical Research (Drs. Bucala and Metz), New York, NY; Intensive Care Unit (Dr. Grant), Western General Hospital, Edinburgh; and Accident and Emergency Department (Dr. Robertson), Royal Infirmary Hospital, Edinburgh, Scotland.
Correspondence to: S.C. Donnelly, Respiratory Medicine Unit, Rayne Laboratory, University of Edinburgh, Teviot Place, Edinburgh, Scotland EH8 9AG
Edinburgh, we have been interested in delineating early specific
inflammatory events associated with ARDS disease progression. We have
previously reported that an elevated interleukin-8 (IL-8) level within
the alveolar airspaces of patients “at-risk” for ARDS is
significantly associated with ARDS disease progression.1
For our trauma “at risk” patients, this was within a mean of 95 min
after the initiating trauma event. This rapid upregulation of IL-8
secretion led us to investigate the role of specific members of the
neuroendocrine system in this process. As part of this work, we
investigated whether migration inhibitory factor (MIF) might play a
role in ARDS pathogenesis.
MIF represents a key modulator of the inflammatory and immune
responses. Recently, it has been shown to override
glucocorticoid-mediated inhibition of cytokine secretion.2–
It is found stored in granular form in corticotropic cells of the
anterior pituitary and is secreted rapidly into the circulation as part
of the stress response.3
BAL samples from both at-risk (n = 41), established ARDS patients
(n = 20) and nonsmoking control subjects (n = 10) were assayed for
MIF via standard enzyme-linked immunosorbent assay. ARDS alveolar cells
were coincubated with either MIF (10 ng/mL) or monoclonal anti-MIF
antibody, and proinflammatory cytokine production (tumor necrosis
factor-α [TNF-α], IL-8) was assayed from collected 12-h
supernatants. In addition, ARDS alveolar cells were pretreated with
dexamethasone (1 μM) and then coincubated with increasing
concentrations of MIF for 12 h. Collected supernatants were then
assayed for TNF-α and IL-8.
Significantly elevated alveolar MIF was found in ARDS patients compared
with control subjects (p =0.0004). Human rMIF was shown to
enhance both TNF-α (212 ± 33%) and IL-8 (162 ± 18%) secretion
from ARDS alveolar cells compared with control untreated cells.
Anti-MIF pretreatment of these cells significantly decreased TNF-α
and IL-8 production from ARDS alveolar cells (−29 ± 6.3% and
−58 ± 23%, respectively). In addition, we demonstrate that MIF
overrides, in a concentration-dependant fashion,
glucocorticoid-mediated inhibition of cytokine secretion in ARDS
alveolar cells. Significantly elevated alveolar MIF was found in those
at-risk patients who progressed to ARDS (n = 10) (mean ± SD:
1,340 ± 998 pg/mL) compared with those who did not (n = 31)
(mean ± SD: 637 ± 541 pg/mL) (p < 0.01). In this study, we
identify MIF for the first time (to our knowledge) in human disease,
and suggest that MIF may act as a mediator that promotes and sustains
the pulmonary inflammatory response in ARDS. Its presence in ARDS may
also represent part of the explanation why corticosteroid treatment has
proved disappointing in established cases of this disease.
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