Correspondence

Acute Oxygen-Sensing Mechanisms

N Engl J Med 2006; 354:975-977March 2, 2006

Article

To the Editor:

The review article by Weir et al. (Nov. 10 issue)1 on acute oxygen-sensing mechanisms omits one of the most important of the mechanisms: the angiotensin-converting–enzyme (ACE) molecule. ACE is enriched in the pulmonary circulation, where it appears to function not only as a mechanosensor2 but also as a reduction–oxidation (redox) sensor.3 A central role for ACE in ventilation–perfusion matching would explain its involvement in lung pathology.4,5 ACE inhibition or angiotensin II blockade may be effective for treating acute and chronic lung diseases, including the acute respiratory distress syndrome, high-altitude pulmonary edema, viral pneumonia, bronchiolitis obliterans, pulmonary fibrosis, lung cancer, and chronic obstructive pulmonary disease.

David W. Moskowitz, M.D.
GenoMed, St. Louis, MO 63132
dwmoskowitz@genomed.com

Dr. Moskowitz is the founder, chief executive officer, and chief medical officer of GenoMed, which owns pending patents on the use of ACE inhibitors and angiotensin-receptor blockers for pulmonary disease.

5 References

1. 1

   Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 2005;353:2042-2055
   Full Text | Web of Science | Medline

2. 2

   Moskowitz DW. Is “somatic“ angiotensin I-converting enzyme a mechanosensor? Diabetes Technol Ther 2002;4:841-858
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   Moskowitz DW, Johnson FE. The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. Curr Top Med Chem 2004;4:1433-1454
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   Moskowitz DW. Is angiotensin I-converting enzyme a “master“ disease gene? Diabetes Technol Ther 2002;4:683-711
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   Moskowitz DW. From pharmacogenomics to improved patient outcomes: angiotensin I-converting enzyme as an example. Diabetes Technol Ther 2002;4:519-532
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To the Editor:

Weir et al. might have mentioned that prolonged and chronic hypoxia modulates ion-channel excitability and has a role in neurodegeneration. Hypoxia leads to the formation of beta-amyloid peptides through amyloidogenic processing of amyloid precursor protein. By up-regulating L-type calcium channels, hypoxia disrupts calcium homeostasis, which may be the basis of the neurotoxicity of beta-amyloid peptides and the development of Alzheimer's disease.1,2 In vitro studies of rat neurons suggest that cholinergic neurons are especially vulnerable to toxicity from beta-amyloid peptides.3 The role of hypoxia in the predisposition to Alzheimer's disease is largely underrecognized.

Sujoy Khan, M.B., B.S.
Scunthorpe General Hospital, Scunthorpe DN15 7BH, United Kingdom

3 References

1. 1

   Kawahara M, Kuroda Y. Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res Bull 2000;53:389-397
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2. 2

   Kar S, Slowikowski SP, Westaway D, Mount HT. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J Psychiatry Neurosci 2004;29:427-441
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3. 3

   Peers C. The G.L. Brown Prize Lecture: hypoxic regulation of ion channel function and expression. Exp Physiol 2002;87:413-422
   Web of Science | Medline

To the Editor:

With regard to the article by Weir et al., we would like to point out that oxygen sensing is also involved in inflammatory and infectious diseases.1,2 Recent evidence suggests a critical role of cellular oxygen-sensing mechanisms during acute immune responses. For example, animals with a conditional knockout of the transcription factor hypoxia-inducible factor 1 (HIF-1) in their myeloid cells show impaired phagocytosis and impaired killing capacity of neutrophils.3 In addition, hypoxia and cellular oxygen-sensing mechanisms are critical to tissue protection during acute colitis.4 Studies of acute bacterial infection have demonstrated a central role of HIF-1 activation leading to increases in hypoxia-induced gene transcription and expression regulated by this oxygen-sensing transcription factor.5 Taken together, such studies suggest a central role for cellular oxygen sensing in the pathogenesis and outcome of inflammatory and infectious diseases.

Holger K. Eltzschig, M.D.
Jorn Karhausen, M.D.
University Hospital for Anesthesiology and Intensive Care Medicine, D-72076 Tübingen, Germany

Volkhard A.J. Kempf, M.D.
Institute for Medical Microbiology and Hygiene, D-72076 Tübingen, Germany
volkhard.kempf@med.uni-tuebingen.de

5 References

1. 1

   Sitkovsky MV, Lukashev D, Apasov S, et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 2004;22:657-682
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2. 2

   Eltzschig HK, Thompson LF, Karhausen J, et al. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 2004;104:3986-3992
   CrossRef | Web of Science | Medline

3. 3

   Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1 alpha is essential for myeloid cell-mediated inflammation. Cell 2003;112:645-657[Erratum, Cell 2003;113:419.]
   CrossRef | Web of Science | Medline

4. 4

   Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 2004;114:1098-1106
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5. 5

   Kempf VAJ, Lebiedziejewski M, Alitalo K, et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation 2005;111:1054-1062
   CrossRef | Web of Science | Medline

To the Editor:

In the article by Weir et al., Figure 4 depicts an NADPH oxidase in the plasma membrane as a source of intracellular reactive oxygen species. The authors acknowledge uncertainties as to the presence or biochemical composition of the presumed NADPH oxidase in such tissues, but the figure poses a serious conceptual problem. If the topology of the oxidase complex has the NADPH-binding domain on the cytoplasmic side of the plasma membrane, thereby facing the source of NADPH (as is the case in the prototypic phagocyte NADPH oxidase1), electrons must be released extracellularly and there reduce molecular oxygen to superoxide ion and its derivatives. For the figure to be accurate, reactive oxygen species must reenter the cell, either through channels or as membrane-soluble agents, such as hydrogen peroxide. Alternatively, the responsible oxidase might be a previously uncharacterized enzyme unrelated to the family of NADPH oxidase proteins and with a novel organization in the membrane. Given this shortcoming in the figure, what is an alternative model that would more accurately depict the mechanism and reflect the underlying biochemistry?

William M. Nauseef, M.D.
University of Iowa, Iowa City, IA 52240
william-nauseef@uiowa.edu

1 References

1. 1

   Taylor RM, Burritt JB, Baniulis D, et al. Site-specific inhibitors of NADPH oxidase activity and structural probes of flavocytochrome b: characterization of six monoclonal antibodies to the p22phox subunit. J Immunol 2004;173:7349-7357
   Web of Science | Medline

Author/Editor Response

Dr. Nauseef points out that the phagocytic NADPH oxidase in the plasma membrane releases reactive oxygen species on the outside of the cell. NADPH oxidase and its homologues may also release reactive oxygen species from intracellular granules, from the endoplasmic reticulum, and into intracellular phagocytic vacuoles.1,2 In the setting of hypoxic pulmonary vasoconstriction, these mechanisms are speculative, and if NADPH oxidase is involved, it seems more likely that hydrogen peroxide would diffuse back into the smooth-muscle cell across the plasma membrane. We have previously shown that NADPH oxidase, containing the gp91^phox subunit, is involved in normoxic generation of reactive oxygen species in mouse lungs.3 However, hypoxic pulmonary vasoconstriction persists when this source of reactive oxygen species is removed, suggesting that it is not essential for initiating that condition. Our work and that of others would favor the mitochondria as a source of signaling reactive oxygen species, at least in the pulmonary arteries.

The oxygen-sensitive factor HIF-1 may play a role in the body's response to inflammation and infection, as suggested by Dr. Eltzschig and colleagues. Although the many actions of HIF-1 are fascinating, they fall outside the scope of our review, which was limited to acute oxygen sensing. It is clear that the chronic response of the pulmonary vasculature to hypoxia does involve HIF activation. Rats that are heterozygous for HIF-1 manifest less chronic hypoxic pulmonary hypertension and have less right ventricular hypertrophy.4

Repeated periods of hypoxia have been associated with an increased incidence of dementia. Chronic hypoxia increases the formation of beta-amyloid peptides, and these in turn increase the expression of L-type calcium channels.5 As stated by Dr. Khan, the loss of calcium homeostasis may cause neurotoxicity and be involved in the pathophysiology of Alzheimer's disease.

Dr. Moskowitz asks whether ACE may play a part in oxygen sensing. Although ACE is active in the pulmonary circulation, we are unaware of rigorous data indicating that it is involved in hypoxic pulmonary vasoconstriction or in oxygen sensing in general. Angiotensin II, in common with many other vasoconstrictors, will enhance hypoxic pulmonary vasoconstriction, but this action is probably distinct from the mechanism of sensing. To date, few data in animals or humans have suggested that ACE inhibitors are beneficial in pulmonary hypertension. Any effect on the pulmonary circulation may be offset by the tendency to cause systemic vasodilation, which can cause hypotension and syncope in patients with pulmonary hypertension.

E. Kenneth Weir, M.D.
Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417
weirx002@umn.edu

José López-Barneo, M.D., Ph.D.
University of Seville, 41013 Seville, Spain

Stephen L. Archer, M.D.
University of Alberta, Edmonton, AB 76G 2B7, Canada

5 References

1. 1

   Karlsson A, Nixon JB, McPhail LC. Phorbol myristate acetate induces neutrophil NADPH-oxidase activity by two separate signal transduction pathways: dependent or independent of phosphatidylinositol 3-kinase. J Leukoc Biol 2000;67:396-404
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2. 2

   Ameziane-El-Hassani R, Morand S, Boucher JL, et al. Dual oxidase-2 has an intrinsic Ca²⁺-dependent H₂O₂-generating activity. J Biol Chem 2005;280:30046-30054
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3. 3

   Archer SL, Reeve HL, Michelakis E, et al. O₂ sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci U S A 1999;96:7944-7949
   CrossRef | Web of Science | Medline

4. 4

   Shimoda LA, Manalo DJ, Sham JS, Semenza GL, Sylvester JT. Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol Lung Cell Mol Physiol 2001;281:L202-L208
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5. 5

   Scragg JL, Fearon IM, Boyle JP, Ball SG, Varadi G, Peers C. Alzheimer's amyloid peptides mediate hypoxic up-regulation of L-type Ca²⁺ channels. FASEB J 2005;19:150-152
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