Biomedical Engineering Reference
In-Depth Information
HYPOXIA-INDUCED MITOGENIC FACTOR (HIMF)
HIMF and Inflammation in the Lung
Using a cDNA microarray from Incyte Genomics, we performed gene expression
proi ling in lungs from mice treated with hypoxia (10%, normal baric) for 4 d.
Data analysis showed that there are 270 genes and expressed sequence tags (ESTs)
signii cantly upregulated out of 9,415 gene elements. h e highest upregulated ESTs
with Genbank accession number AA712003 are increased more than 4-fold in
the hypoxic lung compared with the normoxic controls. Further studies showed
that AA712003 has identical sequence to FIZZ1 and RELMα. We named this
homologue hypoxia-induced mitogenic factor (HIMF) because of its potent
mitogenic action on PMVSMC and its upregulation by hypoxia. HIMF belongs
to the resistin protein families (Holcomb
et al.
2000), whose members encode
proteins of 105-114 amino acids with three domains: (1) an N-terminal signal
sequence, (2) a variable middle portion, and (3) a highly conserved C-terminal
signature sequence that constitutes nearly half of the molecule. h e signature
region of HIMF contains a unique and invariant spacing of the cysteine residues:
C-X
11
-C-X
8
-C-X-C-X
3
-C-X
10
-C-X-C-X-C-X
9
-CC-X
3-6
-END (C represents
cycteine and X is any amino acid residue). h is is reminiscent of the so-called
“EGF repeats” that are characteristic of a number of signaling molecules. Most
important, studies from our laboratory have shown that HIMF enhances VCAM-1
gene production in MLE-12 and endothelial cells. In LPS-treated cells and lung,
HIMF is highly upregulated accompanied by increased monocyte sequestration
in the lung parenchyma and levels of VCAM-1 expression. Administration of
recombinant HIMF into the lung induced robust upregulation of VCAM-1. h ese
i ndings strongly indicate that HIMF may be an important cytokine-like protein
participating in the inl ammatory process via modulation of adhesion molecule
expression in the lung.
HIMF Enhances VCAM-1 Expression in the Lung
To test the hypothesis that HIMF participates in regulation of VCAM-1 expression,
recombinant HIMF protein was administered by intratracheal instillation,
followed by western blot and immunohistochemical staining. As shown in Figs.
1 and 2, HIMF protein instillation signii cantly increased VCAM-1 production in
the lungs and the increased VCAM-1 protein is localized to vascular endothelial,
alveolar type II, and airway epithelial cells compared with control mouse lungs.
