Abstract
Reduction of alveolar PO2 (alveolar hypoxia, AH) may occur in pulmonary diseases such as chronic obstructive pulmonary disease (COPD), or in healthy individuals ascending to altitude. Altitude illnesses may develop in non-acclimatized persons who ascend rapidly. The mechanisms underlying these illnesses are not well understood, and systemic inflammation has been suggested as a possible contributor. Similarly, there is evidence of systemic inflammation in the systemic alterations present in COPD patients, although its role as a causative factor is not clear.
We have observed that AH, induced by breathing 10% O2 produces a rapid (minutes) and widespread micro vascular inflammation in rats and mice. This inflammation has been observed directly in the mesenteric, skeletal muscle, and pial microcirculations. The inflammation is characterized by mast cell degranulation, generation of reactive O2 species, reduced nitric oxide levels, increased leukocyte-endothelial adherence in post-capillary venules, and extravasation of albumin. Activated mast cells stimulate the renin-angiotensin system (RAS) which leads to the inflammatory response via activation of NADPH oxidase. If the animals remain in hypoxia for several days, the inflammation resolves and exposure to lower PO2 does not elicit further inflammation, suggesting that the vascular endothelium has “acclimatized” to hypoxia.
Recent experiments in cremaster microcirculation suggest that the initial trigger of the inflammation is not the reduced tissue PO2, but rather an intermediary re-leased by alveolar macrophages into the circulation. The putative intermediary ac-tivates mast cells, which, in turn, stimulate the local renin-angiotensin system and induce inflammation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Basnyat B, Murdoch BR (2003) High altitude illnesses. Lancet 361:1967–1974.
Hartmann C, Tschopp M, Fischer R, Bidlingmaier C, Riepl R, Tschopp K, Hartmann H, Endres S, Toepfer M (2000) High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 12:246–252.
Klausen T, Olsen NV, Poulsen TD, Richalet JP, Pedersen BK (1997) Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol Occup Physiol 76:480–482.
Kokker M, Kharazmi A, Galbo H, Bygberg I, Pedersen BK (1993) Influence of in vivo hypobaric hypoxia on function of lymphocytes, neurocytes, natural killer cells and cytokines. J Appl Physiol 74:1100–1106.
Møller P, Loft S, Lundby C, Olsen NV (2001) Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans. FASEB J 15:1181–1186.
Beidleman BA, Muza SR, Fluke CS, Cymerman A, Staab JE, Sawka MN, Lewis SF, Skrinar GS (2006) White blood cell and hormonal responses to 4300 m altitude before and after intermittent altitude exposure. Cli Sci 111:163–169.
Choukèr A, Demetz F, Martignoni A, Smith L, Setzer F, Bauer A, Hölzl J, Peter K, Christ F, Thiel M (2005) Strenuous physical exercise inhibits granulocyte activation induced at high altitude. J Appl Physiol 98:640–647.
Tamura DY, Moore EM, Partrick DA, Johnson JL, Offner PJ, Silliman CC (2002) Acute hypoxemia in humans enhances the neutrophil inflammatory response. Shock 17:269–273.
Wood JG, Johnson JS, Mattioli LF, Gonzalez NC (1999a) Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation. J Appl Physiol 87:1734–1740.
Agustí AG (2005) Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:367–370; discussion 371–2.
Gan WQ, Man SF, Senthilselvan A, Sin DD (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59:574–580.
Dix R, Orth T, Allen J, Wood JG, Gonzalez NC (2003) Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules. J Appl Physiol 95:2495–2502.
Shah S, Allen J, Wood JG, Gonzalez NC (2003) Dissociation between microvascular PO2 and hypoxia-induced microvascular inflammation. J Appl Physiol 94:2323–2329.
Mc Donald JT, Gonzalez NC, Wood JG (2003) Mast cell degranulation promotes the cerebral microvascular inflammatory response to hypoxia. (Abstract) FASEB J 17:A1282 (Abstract).
Wood JG, Mattioli LF, Gonzalez NC (1999b) Hypoxia causes leukocyte adherence to mesenteric venules in non-acclimatized rats but not after acclimatization. J Appl Physiol 86:873–881.
Steiner DR, Gonzalez NC, Wood JG (2003) Mast cells mediate the microvascular inflammatory response to hypoxia. J Appl Physiol 94:325–334.
Gonzalez NC, Allen J, Schmidt EJ, Casillan AJ, Orth T, Wood JG (2007b) Role of the renin-angiotensin system in the systemic microvascular inflammation of alveolar hypoxia. Am J Physiol Heart Circ Physiol 292:H2285–H2294.
Wood JG, Johnson JS, Mattioli LF, Gonzalez NC (2000) Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats. J Appl Physiol 89:1561–1568.
Rumsey WL, Vandrkooi JM, Wilson DF (1988) Imaging of Phosphorescence: a novel method for measuring O2 distribution in perfused tissue. Science 241:1649–1651.
Orth T, Allen J, Wood JG , Gonzalez NC (2005) Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules. J Appl Physiol 99:290–297.
Ishii H, Hayashi H, Hogg JC, Fujii T, Goto Y, Sakamoto N, Mukae H, Vincent R, Van Eeden S (2005) Alveolar macrophage-epithelial cell interaction following exposure to atmospheric particles induces the release of mediators involved in monocyte mobilization and recruitment. Resp Res 5:87–98.
Van Eeden DF, Tan WC, Suwa T, Mukae H, Terashima T, Fuji T, Qui D, Vincent R, Hogg JC (2001) Cytokines involved in the systemic inflammatory response induced by particulate matter air pollutants. Am J Respir Crit Care Med 164:826–830.
Van Rooijen N, Sanders A (1994). Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and application. J Immunol Methods 174:83–93.
Gonzalez NC, Allen JA, Blanco VG, Schmidt EJ, van Rooijen N, Wood JW (2007a) Alveolar macrophages are necessary for the systemic inflammation of acute alveolar hypoxia. J Appl Physiol 103:1386–1394.
Acknowledgments
Supported by National Institutes of Health, USA, grant HL39443
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this paper
Cite this paper
Gonzalez, N.C., Wood, J.G. (2010). Alveolar Hypoxia-Induced Systemic Inflammation: What Low PO2 Does and Does Not Do. In: Takahashi, E., Bruley, D. (eds) Oxygen Transport to Tissue XXXI. Advances in Experimental Medicine and Biology, vol 662. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-1241-1_3
Download citation
DOI: https://doi.org/10.1007/978-1-4419-1241-1_3
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4419-1239-8
Online ISBN: 978-1-4419-1241-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)