Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

Zhang, Yinzhong; Talwar, Arunabh; Tsang, Donna; Bruchfeld, Annette; Sadoughi, Ali; Hu, Maowen; Omonuwa, Kennedy; Cheng, Kai; Al‐Abed, Yousef; Miller, Edmund J.

doi:10.2119/molmed.2011.00094

Cited by 64 publications

(52 citation statements)

References 55 publications

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“…Consistent with these findings, pulmonary infiltration of MCT-injected rats chronically treated with the MIF antagonist ISO-1 or with anti-CD74 neutralizing antibodies is substantially reduced. Consistent with our findings, Zhang and colleagues have also reported that MIF plays a critical role in hypoxia-induced PH and that its inhibition may be beneficial in preventing the development and progression of the hypoxic PH (38,39). In addition, Bernhagen and colleagues (9) have demonstrated that the inhibition of CD74 with neutralizing antibodies reduced the MIF-dependent monocyte arrest on ex vivo carotid arteries from apolipoprotein E-deficient (Apoe-/-) mice.…”

supporting

confidence: 87%

Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex

Hiress

Ricard

et al. 2015

Am J Respir Crit Care Med

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supporting

confidence: 87%

Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex

Hiress

Ricard

et al. 2015

Am J Respir Crit Care Med

160

155

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“…2), suggesting that MIF induction is due, at least in part, to the metabolism of ethanol by way of CYP2E1. Another contributor to induction of MIF during ethanol exposure may be related to localized hypoxia in the liver during ethanol metabolism 30, 31. Ischemia‐reperfusion, which results in hypoxia, is associated with increased serum MIF, as well as increased expression of MIF mRNA and protein 11.…”

Section: Discussionmentioning

confidence: 99%

“…Ischemia‐reperfusion, which results in hypoxia, is associated with increased serum MIF, as well as increased expression of MIF mRNA and protein 11. Further, MIF enhances its own expression under hypoxic conditions 30. Taken together, it is likely that ethanol metabolism by way of CYP2E1, in conjunction with localized ethanol‐induced hypoxia in the liver, contribute to increased MIF expression during chronic ethanol feeding.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis

et al. 2013

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MIF, a multi-potent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and non-parenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF−/− mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal; early response) or 25 (32% kcal; chronic response) days. Expression of MIF mRNA was induced at both 4d and 25d of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma ALT and AST were increased in wild-type, but not MIF−/−, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wild-type and MIF−/− to ethanol. Ethanol feeding for 4d increased apoptosis of hepatic macrophages and activated complement in both wild-type and MIF−/− mice. However, TNFα expression was increased only in wild-type mice. This attenuation of TNF-α expression was associated with fewer F4/80+ macrophages in liver of MIF−/− mice. After 25d of ethanol feeding, chemokine expression was increased in wild-type mice, but not MIF−/− mice. Again, this protection was associated with decreased F4/80+ cells in MIF−/− mice after ethanol feeding. Chronic ethanol feeding also sensitized wild-type, but not MIF−/−, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion Taken together, these data indicate that MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol-induced steatosis and hepatocyte damage.

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“…As a result, the measured circulating concentrations of these markers might not reflect the true plasma concentrations (or more relevant local tissue concentrations) during the different hypoxic or hyperoxic exposures, assuming that they would rapidly change in response to altered inspired oxygen concentration. The latter is an oxygen-sensitive archetypical cytokine that has been proposed to mediate hypoxia-induced pulmonary hypertension (Zhang et al 2012) and also plays a role in several aspects of cardiovascular disease (Zernecke et al 2008); the former has been implicated in the diastolic dysfunction that results from global hypoxic vasoconstriction and consecutive increases in right ventricular afterload (Larsen et al 2008). The latter is particularly remarkable in view of the oxidative stress that typically accompanies acute and chronic hypoxic exposures, as verified by the increase in circulating concentrations of the lipid oxidation product 8-isoprostane, and is consistent with earlier observations.…”

Section: Biomarker Measurementsmentioning

confidence: 99%

Changes in acute pulmonary vascular responsiveness to hypoxia during a progressive ascent to high altitude (5300 m)

Luks

Levett

Goss

et al. 2017

Experimental Physiology

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What is the central question of this study? Do the pulmonary vascular responses to hypoxia change during progressive exposure to high altitude and can alterations in these responses be related to changes in concentrations of circulating biomarkers that affect the pulmonary circulation? What is the main finding and its importance? In our field study with healthy volunteers, we demonstrate changes in pulmonary artery pressure suggestive of remodelling in the pulmonary circulation, but find no changes in the acute responsiveness of the pulmonary circulation to changes in oxygenation during 2 weeks of exposure to progressive hypoxia. Pulmonary artery pressure changes were associated with changes in erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. We sought to determine whether changes in pulmonary artery pressure responses to hypoxia suggestive of vascular remodelling occur during progressive exposure to high altitude and whether such alterations are related to changes in concentrations of circulating biomarkers with known or suspected actions on the pulmonary vasculature during ascent. We measured tricuspid valve transvalvular pressure gradients (TVPG) in healthy volunteers breathing air at sea level (London, UK) and in hypoxic conditions simulating the inspired O partial pressures at two locations in Nepal, Namche Bazaar (NB, elevation 3500 m) and Everest Base Camp (EBC, elevation 5300 m). During a subsequent 13 day trek, TVPG was measured at NB and EBC while volunteers breathed air and hyperoxic or hypoxic mixtures simulating the inspired O partial pressures at the other locations. For each location, we determined the slope of the relationship between TVPG and arterial oxygen saturation (SaO2) to estimate the pulmonary vascular response to hypoxia. Mean TVPG breathing air was higher at any SaO2 at EBC than at sea level or NB, but there was no change in the slope of the relationship between SaO2 and TVPG between locations. Nitric oxide availability remained unchanged despite increases in oxidative stress (elevated 8-isoprostane). Erythropoietin, pro-atrial natriuretic peptide and interleukin-18 levels progressively increased on ascent. Associations with TVPG were observed only with erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. Although the increased TVPG for any given SaO2 at EBC suggests that pulmonary vascular remodelling might occur during 2 weeks of progressive hypoxia, the lack of change in the slope of the relationship between TVPG and SaO2 indicates that the acute pulmonary vascular responsiveness to changes in oxygenation does not vary within this time frame.

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Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

Cited by 64 publications

References 55 publications

Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex

Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex

Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis

Changes in acute pulmonary vascular responsiveness to hypoxia during a progressive ascent to high altitude (5300 m)

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