Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Hypoxia-induced mitogenic factor (HIMF), also known as found in inflammatory zone 1 (FIZZ1) and resistin-like molecule α (RELMα), belongs to a novel class of cysteine-rich secreted proteins. It exhibits mitogenic and chemotactic properties during pulmonary hypertension (PH)-associated vascular remodeling as well as inflammatory and fibrogenic properties in the lung. Recent evidence suggests that inflammatory processes may be critical to the development of many forms of PH. We reported previously that HIMF/FIZZ1 promotes pro-inflammatory responses in the lung and lung vasculature, and that the Th2 cytokine interleukin-4 (IL-4) plays a crucial part of this phenomenon. Here, we investigated the mechanism of HIMF/FIZZ1-induced pro-inflammatory responses, specifically in pulmonary endothelial cell (EC) activation and leukocyte recruitment in the lung. We also investigated the effect of Resistin, one of the human homologue of HIMF/FIZZ1, on human pulmonary microvascular EC (PMVEC) activation.
METHODS: We instilled recombinant HIMF via tail vein injection into wild type (WT) control and IL-4 KO mice, and we analyzed the expression of vascular inflammation- and pulmonary arterial hypertension (PAH)-related gene expression, and compared leukocyte infiltration in the lungs of each genotype. We also performed in vivo Matrigel plug vascular formation studies to identify the cell types that were recruited by HIMF/FIZZ1 and participated in its vascular growth response. Lastly, we stimulated mouse or human PMVEC with HIMF/FIZZ1 or Resistin, respectively, and examined the expression of vascular adhesion molecules.
RESULTS: Our results show that HIMF/FIZZ1 induced PAH-related vascular inflammatory marker gene expression in a manner dependent on the Th2 cytokine IL-4. HIMF/FIZZ1 also recruited leukocytes, especially macrophages at the initiation of vascular formation in vivo. In addition, both HIMF/FIZZ1 and Resistin stimulated P-selectin expression in murine and human PMVEC, respectively.
CONCLUSIONS: Our results suggest that HIMF/FIZZ1 and Resistin play a critical role in pulmonary inflammation by activating pulmonary EC and subsequent leukocyte recruitment into the pulmonary vascular beds. These phenomena may contribute to an increased risk for the development of PH and other pulmonary vascular diseases.