Hypoxic pulmonary blood flow redistribution and arterial oxygenation in endotoxin-challenged NOS2-deficient mice
Roman Ullrich, … , Wolfgang Steudel, Warren M. Zapol
Roman Ullrich, … , Wolfgang Steudel, Warren M. Zapol
Published November 15, 1999
Citation Information: J Clin Invest. 1999;104(10):1421-1429. https://doi.org/10.1172/JCI6590.
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Article

Hypoxic pulmonary blood flow redistribution and arterial oxygenation in endotoxin-challenged NOS2-deficient mice

Abstract

Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing arterial oxygenation and enhancing hypoxemia. Endotoxin induces nitric oxide (NO) production by NO synthase 2 (NOS2). To assess the role of NO and NOS2 in the impairment of HPV during endotoxemia, we measured in vivo the distribution of total pulmonary blood flow (QPA) between the right (QRPA) and left (QLPA) pulmonary arteries before and after left mainstem bronchus occlusion (LMBO) in mice with and without a congenital deficiency of NOS2. LMBO reduced QLPA/QPA equally in saline-treated wild-type and NOS2-deficient mice. However, prior challenge with Escherichia coli endotoxin markedly impaired the ability of LMBO to reduce QLPA/QPA in wild-type, but not in NOS2-deficient, mice. After endotoxin challenge and LMBO, systemic oxygenation was impaired to a greater extent in wild-type than in NOS2-deficient mice. When administered shortly after endotoxin treatment, the selective NOS2 inhibitor L-NIL preserved HPV in wild-type mice. High concentrations of inhaled NO attenuated HPV in NOS2-deficient mice challenged with endotoxin. These findings demonstrate that increased pulmonary NO levels (produced by NOS2 or inhaled at high levels from exogenous sources) are necessary during the septic process to impair HPV, ventilation/perfusion matching and arterial oxygenation in a murine sepsis model.

Authors

Roman Ullrich, Kenneth D. Bloch, Fumito Ichinose, Wolfgang Steudel, Warren M. Zapol

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Figure 2

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(a) Correlation of percent pulmonary blood flow to the left or right lun...
(a) Correlation of percent pulmonary blood flow to the left or right lung assessed by intravenous injection of fluorescent microspheres (15 μm) and by simultaneous measurement of QRPA with an ultrasonic flow probe. In the latter method, differential blood flow distribution between the right and left pulmonary artery was assessed by transient occlusion of the left pulmonary artery, as described in the legend to Figure 1. Values are expressed as the fractional flow to the right or left lung before and after LMBO (saline-treated wild-type mice; n = 4). Note the close agreement between the 2 methods (r2 = 0.967). (b) The left lung pulmonary flow-pressure relationship before (baseline) and after 5 minutes of LMBO in saline-treated wild-type mice (n = 6). Note the significant increase of the slope, which represents an increased incremental left lung pulmonary vascular resistance induced by LMBO. Left pulmonary artery flow (QLPA) was measured by an ultrasonic flow probe, and the slopes were generated by reducing QPA with a transient occlusion of the inferior vena cava (P < 0.05, slope differs versus baseline). (c) Changes in total left lung pulmonary vascular resistance (TLPVR) during re-expansion of the collapsed left lung in saline-treated wild-type mice (n = 3). The left lung was inflated by a continuous injection of 5% CO2 in N2 up to a peak inspiratory pressure of 30 cm H2O. Values are expressed as a linear regression of all data points with the respective 95% confidence intervals.