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Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations
Li Gao1, Carlos Flores, Shwu Fan-Ma
1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.
Abstract:
The macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine central to the response to endotoxemia, is a putative biomarker in acute lung injury (ALI). To explore MIF as a molecular target and candidate gene in ALI, the MIF gene and protein expression were examined in murine and canine models of ALI (high tidal volume mechanical ventilation, endotoxin exposure) and in patients with either sepsis or sepsis-induced ALI. MIF gene expression and protein levels were significantly increased in each ALI model, with serum MIF levels significantly higher in patients with either sepsis or ALI compared with healthy controls (African- and European-descent). The association of 8 MIF gene polymorphisms (single-nucleotide polymorphisms (SNPs)) (within a 9.7-kb interval on chromosome 22q11.23) with the development of sepsis and ALI in European-descent and African-descent populations was studied next. Genotyping in 506 DNA samples (sepsis patients, sepsis-associated ALI patients, and healthy controls) revealed haplotypes located in the 3' end of the MIF gene, but not individual SNPs, associated with sepsis and ALI in both populations. These data, generated via functional genomic and genetic approaches, suggest that MIF is a relevant molecular target in ALI.
Insights
Macrophage migration inhibitory factor (MIF) is elevated in acute lung injury (ALI) and sepsis. Genetic analysis revealed MIF gene haplotypes, not individual SNPs, are associated with ALI development in diverse populations.
Area of Science:
- Immunology
- Genetics
- Pulmonology
Background:
- Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in endotoxemia and acute lung injury (ALI).
- MIF's role as a potential biomarker and therapeutic target in ALI warrants further investigation.
Purpose of the Study:
- To investigate MIF gene and protein expression in experimental ALI models and human sepsis/ALI.
- To examine the association of MIF gene polymorphisms with sepsis and ALI susceptibility in different ethnic groups.
Main Methods:
- Analysis of MIF expression in murine and canine ALI models (mechanical ventilation, endotoxin exposure).
- Measurement of serum MIF levels in human sepsis and ALI patients versus healthy controls.
- Genotyping of 8 MIF single-nucleotide polymorphisms (SNPs) and haplotype analysis in 506 DNA samples from diverse populations.
Main Results:
- MIF gene and protein expression were significantly upregulated in all ALI models.
- Serum MIF levels were markedly higher in sepsis and ALI patients compared to controls.
- MIF gene haplotypes, particularly in the 3' region, were associated with sepsis and ALI development across ethnic groups, while individual SNPs were not.
Conclusions:
- MIF is a relevant molecular target in ALI, with its expression significantly increased in disease states.
- MIF gene haplotypes, rather than individual SNPs, are linked to sepsis and ALI susceptibility.
- These findings support MIF's role in ALI pathogenesis and its potential as a biomarker.
