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Ebook The pulmonary endothelium: Part 2

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Ebook The pulmonary endothelium: Part 2

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2own University, Providence VA Medical Center, Providence, Rl, USAINTRODUCTIONCellular responses to oxygen arc critical lor normal energy metabolism, m

ediator release, proliferation, and survival. The lung has three sources of oxygen - from inspired gas. from the bronchial circulation, and from syste Ebook The pulmonary endothelium: Part 2

mic venous blood returned to the lung via the right ventricle. The endothelia of conduit pulmonary arteries and veins are not exposed to oxygen in alv

Ebook The pulmonary endothelium: Part 2

eoli and the endothelium of small pulmonary blood vessels does not benefit from the bronchial circulation. The lung has unique responses to hypoxia -

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2 into tissues (pulmonary edema, sec Chapters 8. 21. and 24). Owing to these unique pulmonary physiologic responses to hypoxia, in this chapter we focu

s on the effects of hypoxia on pulmonary microvascular and arterial endothelium. Less is known about effects of hypoxia on pulmonary venous endotheliu Ebook The pulmonary endothelium: Part 2

m and endothelium of bronchial vessels (see Chapter 14).Hypoxia is generally defined as a pO, less than 60torr or blood oxygen saturation less than 90

Ebook The pulmonary endothelium: Part 2

%. based on the sigmoid shape of the oxyhemoglobin desaturation curve. However, in the lung, endothelium of large pulmonary arteries is “normally** ex

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2and alveolar pO; of about 100torr at sea level. Thus, it is not surprising that there is heterogeneity in the response of lung vascular endothelium to

hypoxia, depending upon the type of blood vessel.Studies utilizing cultured pulmonary ECs have been very important in understanding responses to hypo Ebook The pulmonary endothelium: Part 2

xia. However, studies of cultured cells are confounded bythe fact that tissue culture media do not have the same oxygen carrying capacity as hemoglobi

Ebook The pulmonary endothelium: Part 2

n, oxygen can diffuse through tissue culture plastic, and long-term studies of hypoxia may necessitate intermittent return of cultures to room air con

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2ssary to expose cultured ECs to oxygen concentrations of 3% or less to achieve a tissue culture media pOj of less than 60torr. In addition, it is like

ly that intermittent hypoxia has more profound effects on reactive oxygen species (ROS) than sustained hypoxia 1|. Thus, interpretation of cultured ce Ebook The pulmonary endothelium: Part 2

ll Studies requires careful consideration of experimental conditions.HYPOXIA AND PULMONARY EC METABOLISM, VIABILITY, AND PROLIFERATIONIn an early stud

Ebook The pulmonary endothelium: Part 2

y from Una Ryan's laboratory. Cum-miskey Cl al. compared responses to hypoxia of bovine pulmonary artery ECs (BPAECs) and bovine aortic ECs I'BAECs) w

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2me activity upon exposure to pOj 15 torr for 48-96 h. but found no differences between the two cultured cell types. They noted increased glycolytic en

zyme activity in freshly isolated intimal strips from bovine pulmonary artery when compared to aorta strips, suggesting that increased glycolysis is a Ebook The pulmonary endothelium: Part 2

lso seen under hypoxic conditions in vivo.Lee and Fanburg reported that BPAECs exposed to 3 or 0% oxygen for up to 72 h displayed decreased cell proli

Ebook The pulmonary endothelium: Part 2

feration and increased lactate release, but no change in ATP content, indicating a capacity to respondThe Pulmonary Endothelium: Function in health an

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2to hypoxia with glycolysis (3J. Tretyakov and Farber compared hypoxia-tolerant BPAECs to immortalized opossum renal tubular ECs. which are more sensit

ive to hypoxia (4). They found that the pulmonary artery cells exposed to 0% oxygen for up to 18 h were not damaged, displayed increased adenosine and Ebook The pulmonary endothelium: Part 2

guanosine uptake, and did not decrease cell ATP levels over 18 h hypoxic exposure. Farber et al. have further demonstrated that hypoxia-tolerant cult

Ebook The pulmonary endothelium: Part 2

ured main pulmonary artery endothelial cells express a specific set of stress proteins |5|, including glyceraldehyde 3-phosphate dehydrogenase |6|. no

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2tolerant of hypoxia and can uprcgulatc enzymes that enhance glycolytic capacity and activity of the transcription factor hypoxia-inducible factor (HIF

)-lu |9|.Farber et al. have demonstrated that BPAECs anti BAECs arc both capable of proliferation and retain responsiveness to hypoxic stimuli when cu Ebook The pulmonary endothelium: Part 2

ltured long-term (5 days to 16 weeks) under hypoxic conditions (4. 10. 111. However, the rate of cell proliferation is slowed by hypoxia. Interestingl

Ebook The pulmonary endothelium: Part 2

y, lung microvascular ECs have recently been reported to have a proproliferative and vascu-logenic phenotype (12. 13J. Since ECs horn lungs of patient

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2e is a correlation between EC proliferative capacity and bioenergetics.In summary. ECs from conduit pulmonary arteries are tolerant of hypoxia, and ar

c able to enhance glycolysis and proliferate under hypoxic conditions. Further research is needed to determine if there is heterogeneity in these resp Ebook The pulmonary endothelium: Part 2

onses among ECs from different parts of the pulmonary vasculature (see Chapter 9).HYPOXIA SENSOR(S)The pulmonary EC sensor(s) for hypoxia are not well

Ebook The pulmonary endothelium: Part 2

described. The pulmonary microvascular EC is appropriately positioned to sense alveolar hypoxia, thereby stimulating hypoxic pulmonary vasoconstricti

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2sensor cell for hypoxic vasoconstriction, while the EC is capable of modulating the vasoconstrictor response by mediator release (see Chapters 6 and 1

2) 115. 16|. Nevertheless, it is useful to review' the various hypoxia sensors that have been proposed since it is possible that these sensors also fu Ebook The pulmonary endothelium: Part 2

nction in lung ECs (Table 18.1).Ward has categorized putative oxygen sensors as bioenergetic oxygen sensing mechanisms and biosynthetic oxygen sensing

Ebook The pulmonary endothelium: Part 2

mechanisms 117], Among theTable 18.1 Candidates for hypoxia sensorsBioenergetic sensing mechanismsMitochondrial ROSATP productionRedox stateBiosynthe

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2abioenergetic sensors are mitochondrial ROS production. ATP production, and redox state (see Chapter 17). There is controversy as to whether hypoxia i

s sensed via increased mitochondrial ROS production from electron transport 118] or via decreased mitochondrial ROS production resulting in a more red Ebook The pulmonary endothelium: Part 2

uced redox state and inhibition of Cb-sensitive K. channels 116|. Previously investigators used chemical inhibitors of oxidative phosphorylation to as

Ebook The pulmonary endothelium: Part 2

sess the role of ATP production in oxygen sensing 119]. However, the moderate degrees of hypoxia that elicit physiologically significant responses arc

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2ong the biosynthetic sensing mechanisms are NADPH oxidases (NOXs). inhibition of which could result in decreased ROS production. However, mice deficie

nt in the gp91 ^'“-containing NOX, NOX2. had decreased ROS production, but preserved pulmonary hypoxic vasoconstriction [I6|. Pulmonary EC NOXs arc si Ebook The pulmonary endothelium: Part 2

milar to phagocyte NOXs and have been shown to play a role in ROS production in a variety of circumstances, such as inflammation and ischemia-reperfus

Ebook The pulmonary endothelium: Part 2

ion injury (see Chapter 17). However, there is no evidence that EC NOXs arc important in sensing of hypoxia.Heme oxygenases. HO-1. -2, and -3. have be

18Hypoxia and the Pulmonary EndotheliumMatthew Jankowich, Gaurav choudhary and Sharon RoundsVascular Research Laboratory, Alpert Medical School of Bro

Ebook The pulmonary endothelium: Part 2 are expressed in pulmonary arteries [20J. hl rat PAECs. HO-1 has been localized to plasma membrane caveolae in association with caveolin-i |21|. Thus

. EC caveolae may act as a functional unit for HO-1 activity with modulation by cavcolin-l. Il is possible that HOs modulate pulmonary vasoconstrictor Ebook The pulmonary endothelium: Part 2

hypoxic responses via the product CO stimulating production of vasoconstrictor, endothelin |20|. However, knockdown or inhibition of HO-1 and -2 did

Ebook The pulmonary endothelium: Part 2

not prevent hypoxic vasoconstriction of pulmonary arteries [20].OTHER EFFECTS OF HYPOXIA ON PULMONARY ENDOTHELIUM

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