Acute Hypobaric Hypoxia (5486 m) Induces Greater Pulmonary HIF-1 Activation in Hilltop Compared to Madison Rats

Engebretsen, Barbara J.; Irwin, David; Valdez, Maria E.; O'Donovan, M.K.; Tucker, Adam; Patot, Martha C. Tissot van

doi:10.1089/ham.2007.1031

Cited by 26 publications

(15 citation statements)

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“…Uncontrolled HIF activity can lead to endothelial cell dysfunction and pulmonary vascular leakage in vivo and in vitro (8,26,27). Our data showed that the knockdown of HIF-1a exerted a minimal effect on attenuating Hb-induced endothelial cell permeability.…”

Section: Tlr4 (mentioning

confidence: 65%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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The release of hemoglobin (Hb) with hemolysis causes vascular dysfunction. New evidence implicates Hb-induced NF-kB and hypoxia inducible factor (HIF) activation, which may be under the control of a Toll-like receptor (TLR)-signaling pathway. Nearly all TLR-signaling pathways activate the myeloid differentiation primary response gene-88 (MyD88) that regulates NF-kB. We hypothesized that the differing transition states of Hb influence endothelial cell permeability via NF-kB activation and HIF regulation through a MyD88-dependent pathway. In cultured human dermal microvascular endothelial cells (HMECs-1), we examined the effects of Hb in the ferrous (HbFe 21 ), ferric (HbFe 31 ), and ferryl (HbFe 41 ) transition states on NF-kB and HIF activity, HIF-1a and HIF-2a mRNA upregulation, and monolayer permeability, in the presence or absence of TLR4, MyD88, NF-kB, or HIF inhibition, as well as superoxide dismutase (SOD) and catalase. Our data showed that cell-free Hb, in each transition state, induced NF-kB and HIF activity, up-regulated HIF-1a and HIF-2a mRNA, and increased HMEC-1 permeability. The blockade of either MyD88 or NF-kB, but not TLR4, attenuated Hb-induced HIF activity, the up-regulation HIF-1 and HIF-2a mRNA, and HMEC-1 permeability. The inhibition of HIF activity exerted less of an effect on Hb-induced monolayer permeability. Moreover, SOD and catalase attenuated NF-kB, HIF activity, and monolayer permeability. Our results demonstrate that Hb-induced NF-kB and HIF are regulated by two mechanisms, either MyD88 activation or Hb transition state-induced ROS formation, that influence HMEC-1 permeability.Keywords: hemolytic disease; NF-kB; Toll-like receptors; MyD88; sicklecell disease Humans with chronic vascular inflammation and vasoconstriction develop progressive endothelial dysfunction and vascular diseases (e.g., pulmonary arterial hypertension, atherosclerosis, and sickle-cell disease) (1, 2). Vascular diseases develop in the face of chronic hemolysis, as occurs with hemoglobinopathies (including sickle-cell disease), or with the intermittent release of low to moderate levels of plasma-free hemoglobin (Hb), as may be seen in atherosclerosis with intraplaque hemorrhage.Low to moderate levels of plasma-free Hb may, in part, mediate these diseases (1-4). However, studies to date have not fully addressed the complete mechanisms responsible for Hb-induced vascular dysfunction.The a 2 b 2 tetramers of Hb transition safely and effectively between the relaxed (oxy) and tense (deoxy) conformational states, and the oxidation of Hb is controlled by red blood cell catalase, superoxide dismutase (SOD), and ferric Hb reductase. However, after their release from the red blood cell, Hb tetramers and dimers can be oxidized from ferrous (HbFe 21 ) to ferric (HbFe 31 ) (3-5). In theory, HbFe 31 in local tissue environments may react with hydrogen peroxide (H 2 O 2 ) to transition between the ferryl (HbFe 41 ) and HbFe 31 states, leading to heme release, globin chain denaturation, and globin chain crosslinking (4, 5). Oxid...

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Section: Tlr4 (mentioning

confidence: 65%

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Lisk¹,

Kominsky²,

Ehrentraut³

et al. 2013

Am J Respir Cell Mol Biol

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“…In the exercise groups (in either hypoxia or normoxia), the rats walked for 48 h but were allowed to stop for 15-20 min every 4 h, so they could have access to food or water. It is important to note that the rats were, however, continuously exposed to hypoxia during 48 h. All procedures were performed in the main chamber that the investigator could access through an independently controlled antechamber where the pressure was set at 470.48 Torr (<3,800 m) [21]. When pressure inside the main chamber decreased to 3,800 m, the investigator could enter the main chamber to check the rats.…”

Section: Experimental and Control Groupsmentioning

confidence: 99%

“…The following procedure was performed in the main chamber with pressure equivalent to 3,800 m for investigators safety [21]. After anaesthesia (intraperitoneal injection of 10% chloral hydrate, 3 mg?kg -1 ; Sinopharm Chemical Reagent Co., Ltd, Shanghai, China), blood was quickly collected by direct puncture and sampling from the left ventricle using heparinised syringes.…”

Section: Arterial Blood Gasesmentioning

confidence: 99%

“…To date, rabbit, sheep, dogs and ferrets have been used to develop HAPE animal AFFILIATIONS *Dept of Pulmonary Medicine, Zhongshan Hospital, Fudan University, models but the results were neither consistent nor reproducible [18][19][20]. Rats have also been used in a number of studies, but either required endotoxin priming [19], exposure to severe hypoxia (236 Torr, 9,000 m) or the use of specific rat strains such as the Madison strain which has a high susceptibility to the induction of HAPE [15,21]. Some studies on pigs showed findings consistent with onset of HAPE when they were exposed to normobaric hypoxia [22], but no convincing histological evidence was provided.…”

mentioning

confidence: 99%

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Stress failure plays a major role in the development of high-altitude pulmonary oedema in rats

Bai

She²,

Goolaerts³

et al. 2009

Eur Respir J

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Hypoxia and exertion are considered as the two main factors in the development of high-altitude pulmonary oedema (HAPE), however its pathophysiology remains unclear. Therefore, we established a model in which 32 Sprague-Dawley rats were randomly assigned to normoxic rest, hypoxic rest, normoxic exercise and hypoxic exercise.An altitude of 4,700 m was simulated using hypobaric hypoxia, while exercise consisted 48 h walk with 15-20 min breaks every 4 h. Arterial blood gas, bronchoalveolar lavage (BAL), lung wetto-dry weight (W/D) ratio and histological measurements were conducted on each animal.In rats exercising in hypoxia, BAL protein and lung W/D ratio were significantly increased but no changes in BAL leukotriene B 4 and immunoglobulin M were observed. In the same group, lung histology showed typical haemorrhagic lung oedema and disruption of both alveolar epithelium and capillary endothelium while hypoxia or exertion alone only induced slight endothelium and epithelium swelling/disruption.Our study established a direct link between histological and physiological evidence of HAPElike symptoms and we demonstrated that hypoxia and exertion can synergistically induce HAPElike symptoms in Sprague-Dawley rats without inducing lung inflammation. We therefore propose that alveolar epithelium and capillary endothelium stress failure play a major role in the development of HAPE.KEYWORDS: Exercise, high-altitude pulmonary oedema, hypobaric hypoxia, rat model, stress failure H igh-altitude pulmonary oedema (HAPE) is a potentially fatal condition that may affect nonacclimatised individuals who ascend rapidly to altitudes .3,000 m [1, 2]. Approximately 2% of individuals exposed to high altitude are affected severely enough by HAPE to seek treatment [3]. However, the incidence of sub-clinical HAPE may be as high as 75% in individuals travelling at an altitude .4,500 m [4].Hypoxia and exertion have been identified as the two main factors in HAPE development [5]. However, the exact mechanisms that trigger the development of HAPE are not completely understood. Although factors such as inflammation and decreased alveolar fluid clearance are thought to be important in HAPE pathophysiology [6][7][8][9], pulmonary capillary stress failure, which results from an uneven hypoxic pulmonary vascoconstriction [10,11], has been suggested to be the primary inciting mechanism. Indeed, increased pulmonary capillary transmural pressure [12][13][14] causes the rupture of the alveolocapillary membrane [15], allowing the flooding of the alveolar space with a protein rich and haemorrhagic oedema fluid. HOPKINS et al. [16] found evidence of stress failure in exercising humans under hypoxic conditions, and SWENSON et al. [17] showed the presence of red blood cells as well as increased protein concentration in BAL fluid from humans with HAPE, without significant changes in BAL cytokines. However, whether pulmonary capillary stress failure is the primary mechanism in the development of HAPE is not conclusive since direct evidence of capi...

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“…Iron supplementation and iron chelation reduce and increase HPV respectively [ 69 , 70 ], possibly via altered HIF metabolism [ 71 ]. In two rat strains with differing pulmonary hypoxic responses, HIF-1 activity and HIF-mediated protein expression were higher in the strain with lesser pulmonary hypertension [ 72 ]. In contrast, mice with heterozygous HIF 1-alpha defi ciency have weaker acute and chronic hypoxic responses in isolated pulmonary vascular smooth myocytes and pulmonary vessels than wild type mice [ 73 , 74 ].…”

Section: Neuro-humoral Responsesmentioning

confidence: 99%

High-Altitude Pulmonary Edema (HAPE)

Schoene

Swenson

2013

High Altitude

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Much of the clinical impact of acute altitude illnesses stems from fl uid accumulation in interstitial spaces and nowhere is this more apparent than in the lungs as the edema escapes into the alveoli to cause life-threatening hypoxemia. This chapter will update our knowledge of HAPE over the past decade about the vasculature, alveolar epithelium, innervation, immune response, and genetics of the lung in hypoxia, as well as prophylactic and therapeutic strategies to reduce the toll of this most common alpine life-threatening illness. 406extend to HPV, would predict greater HAPE susceptibility. Although HAPE can develop in sedentary persons, exercise [ 6 ] and its pulmonary hemodynamic consequences (discussed below) are important precipitating factors.Symptoms, signs, and physiologic changes in lung function typical of pulmonary edema [ 1 -3 , 7 ] evolve in 2-4 days after ascent, often preceded or accompanying AMS (see Chap. 20 ), but can occur later with further ascent. Arterial saturations can fall as low as 40 % and PaO 2 s in the low 20 mmHg range. HAPE in its severest stage with profound hypoxemia can lead to high-altitude cerebral edema [ 8 ]. Repeat occurrences of HAPE do not always involve infi ltrates in the same areas, which suggests that fi xed structural aspects of lung parenchyma or vessels do not account for the timing of edema or its locale [ 9 ]. A special exception is unilateral absence of a pulmonary artery, in which edema always occurs in the contralateral lung receiving the entire cardiac output [ 10 ].It has been suggested that many persons (50-75 %) may have subclinical HAPE that resolves spontaneously despite remaining at altitude [ 11 -13 ]. This incidence equals that of AMS, which itself can cause mild gas exchange impairment [ 14 ] by unknown mechanisms perhaps related to altered autonomic infl uences on the pulmonary circulation and/or airways leading to ventilation-perfusion mismatching. Subclinical HAPE may be considerably overestimated without radiography [ 15 ] because indirect measures of interstitial edema such as spirometry, closing volume, and/or transthoracic impedance can vary for other reasons related to mountaineering including intense exercise and increased cardiac output, cold/dry air-induced bronchoconstriction, and hypocapnia [ 16 ]. With radiographically mild HAPE, only modest abnormalities were detectable [ 15 ] suggesting many lung function parameters are not sensitive enough to detect small changes in interstitial fl uid and may require highresolution tissue density measurements by CT or MR imaging. Reentry HAPE occurs when longterm high-altitude residents return to high altitude following a brief low-altitude sojourn. It has a strong familial basis and affl icts children more than adults [ 17 ], perhaps due to a twofold greater magnitude of HPV in preteen children (age 6-9) compared to teenagers (age 14-16) when tested 40 h after ascent to high altitude [ 18 ]. PathophysiologyFrom its fi rst modern descriptions, pulmonary hypertension and HAPE have been inex...

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Acute Hypobaric Hypoxia (5486 m) Induces Greater Pulmonary HIF-1 Activation in Hilltop Compared to Madison Rats

Cited by 26 publications

References 44 publications

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Hemoglobin-Induced Endothelial Cell Permeability Is Controlled, in Part, via a Myeloid Differentiation Primary Response Gene–88–Dependent Signaling Mechanism

Stress failure plays a major role in the development of high-altitude pulmonary oedema in rats

High-Altitude Pulmonary Edema (HAPE)

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