scholarly journals The effects of genetic deletion of Macrophage migration inhibitory factor on the chronically hypoxic pulmonary circulation

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402094135
Author(s):  
Lili Li ◽  
Maojia Xu ◽  
Simon C. Rowan ◽  
Katherine Howell ◽  
Adam Russell-Hallinan ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Hypoxic Pulmonary Hypertension ◽  
Major Mechanism ◽  
Isolated Lungs

While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout ( MIF–/–) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice ( MIF+/+). Following exposure to hypoxia for three weeks, isolated lungs from MIF–/– mice had significantly higher pulmonary vascular resistance than those from MIF+/+ mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF–/– mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.

scholarly journals Role of Macrophage Migration Inhibitory Factor in the Proliferation of Smooth Muscle Cell in Pulmonary Hypertension

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Bo Zhang ◽  
Min Shen ◽  
Min Xu ◽  
Li-Li Liu ◽  
Ying Luo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Heart Diseases ◽  
Pulmonary Arteries ◽  
Underlying Mechanism ◽  
Inhibitory Factor ◽  
Macrophage Migration

Pulmonary hypertension (PH) contributes to the mortality of patients with lung and heart diseases. However, the underlying mechanism has not been completely elucidated. Accumulating evidence suggests that inflammatory response may be involved in the pathogenesis of PH. Macrophage migration inhibitory factor (MIF) is a critical upstream inflammatory mediator which promotes a broad range of pathophysiological processes. The aim of the study was to investigate the role of MIF in the pulmonary vascular remodeling of hypoxia-induced PH. We found that MIF mRNA and protein expression was increased in the lung tissues from hypoxic pulmonary hypertensive rats. Intensive immunoreactivity for MIF was observed in smooth muscle cells of large pulmonary arteries (PAs), endothelial cells of small PAs, and inflammatory cells of hypoxic lungs. MIF participated in the hypoxia-induced PASMCs proliferation, and it could directly stimulate proliferation of these cells. MIF-induced enhanced growth of PASMCs was attenuated by MEK and JNK inhibitor. Besides, MIF antagonist ISO-1 suppressed the ERK1/2 and JNK phosphorylation induced by MIF. In conclusion, the current finding suggested that MIF may act on the proliferation of PASMCs through the activation of the ERK1/2 and JNK pathways, which contributes to hypoxic pulmonary hypertension.

scholarly journals Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Nair Y. Maeda ◽  
Vera D. Aiello ◽  
Paulo C. Santos ◽  
Ana M. Thomaz ◽  
Luiz J. Kajita ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Pulmonary Arteries ◽  
Macrophage Migration ◽  
Carbamyl Phosphate ◽  
Carbamyl Phosphate Synthetase ◽  
Medial Hypertrophy

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units×m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p=0.045), particularly in the high-PVR group (n=16) (p=0.022) and in subjects with the AC CPSI T1405N genotype (n=16) compared to those with the CC genotype (n=25) (p=0.017). Patients with high-PVR/AC-genotype profile (n=9) had the highest MIF levels (p=0.030 compared with the high-PBF/CC-genotype subgroup, n=18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p=0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.

scholarly journals Multiple roles of macrophage migration inhibitory factor in pulmonary hypertension

2020 ◽  
Vol 318 (1) ◽  
pp. L1-L9 ◽  
Author(s):  
Gael Jalce ◽  
Christophe Guignabert
Keyword(s):  
Pulmonary Hypertension ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Scientific Evidence ◽  
Pulmonary Arteries ◽  
Inhibitory Factor ◽  
Pulmonary Vasculature ◽  
Macrophage Migration ◽  
Multifactorial Diseases ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) is a life-threatening condition arising from the loss and obstructive remodeling of the pulmonary arteries, leading to the sustained elevation of pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) and subsequently right ventricular (RV) failure and death. PH encompasses a group of multifactorial diseases, such as pulmonary arterial hypertension (PAH) and chronic thromboembolic PH, for which there is no treatment that can stop or reverse the progression of remodeling of the pulmonary vasculature. The identification of new molecular targets for the development of more effective drugs is thus urgently needed. In this context, macrophage migration inhibitory factor (MIF), a pleiotropic upstream proinflammatory mediator, is emerging as a promising molecular target, as it contributes to perivascular inflammation and pulmonary arterial remodeling, two key hallmarks of PAH that are not specifically targeted by currently approved therapies. The objective of this review is to summarize the scientific evidence on the pathogenic roles of MIF and its potential as a biomarker and therapeutic target in PH/PAH.

scholarly journals Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

2011 ◽  
Vol 18 (2) ◽  
pp. 215-223 ◽  
Author(s):  
Yinzhong Zhang ◽  
Arunabh Talwar ◽  
Donna Tsang ◽  
Annette Bruchfeld ◽  
Ali Sadoughi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Macrophage Migration
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