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. 2013 Jul 15;188(2):167-78.
doi: 10.1164/rccm.201301-0185OC.

Markers of Vascular Perturbation Correlate With Airway Structural Change in Asthma

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Free PMC article

Markers of Vascular Perturbation Correlate With Airway Structural Change in Asthma

Mats W Johansson et al. Am J Respir Crit Care Med. .
Free PMC article

Abstract

Rationale: Air trapping and ventilation defects on imaging are characteristics of asthma. Airway wall thickening occurs in asthma and is associated with increased bronchial vascularity and vascular permeability. Vascular endothelial cell products have not been explored as a surrogate to mark structural airway changes in asthma.

Objectives: Determine whether reporters of vascular endothelial cell perturbation correlate with airway imaging metrics in patients with asthma of varying severity.

Methods: Plasma from Severe Asthma Research Program subjects was analyzed by ELISAs for soluble von Willebrand factor mature protein (VWF:Ag) and propeptide (VWFpp), P-selectin, and platelet factor 4. Additional subjects were analyzed over 48 hours after whole-lung antigen challenge. We calculated ventilation defect volume by hyperpolarized helium-3 magnetic resonance imaging and areas of low signal density by multidetector computed tomography (less than -856 Hounsfield units [HU] at functional residual capacity and -950 HU at total lung capacity [TLC]).

Measurements and main results: VWFpp and VWFpp/Ag ratio correlated with and predicted greater percentage defect volume on hyperpolarized helium-3 magnetic resonance imaging. P-selectin correlated with and predicted greater area of low density on chest multidetector computed tomography less than -950 HU at TLC. Platelet factor 4 did not correlate. Following whole-lung antigen challenge, variation in VWFpp, VWFpp/Ag, and P-selectin among time-points was less than that among subjects, indicating stability and repeatability of the measurements.

Conclusions: Plasma VWFpp and P-selectin may be useful as surrogates of functional and structural defects that are evident on imaging. The results raise important questions about why VWFpp and P-selectin are associated specifically with different imaging abnormalities.

Figures

<i>Figure 1.</i>
Figure 1.
Hyperpolarized helium-3 magnetic resonance imaging (HPHe-MRI) (A and B) and multidetector computed tomography (MDCT) (C and D) of four Severe Asthma Research Program subjects with asthma illustrating the associations between von Willebrand factor propeptide (VWFpp), VWFpp/VWF mature protein (VWF:Ag), or P-selectin and abnormalities. (A) Subject with nonsevere asthma, P-selectin of 18 ng/ml, VWFpp of 171 U/dl, VWFpp/Ag of 1.65, and defect volume on HPHe-MRI of 11.1%, above the median of 1.8% for all subjects with asthma. Red arrows = defective regions. (B) Subject with severe asthma, P-selectin of 16 ng/ml, VWFpp of 109 U/dl, VWFpp/Ag of 0.68, and no detectable ventilation defect (0.0%) on HPHe-MRI. (C) Subject with severe asthma, P-selectin of 48 ng/ml, VWFpp of 103 U/dl, VWFpp/Ag of 1.10, and area of signal density on MDCT less than −950 HU at TLC of 7.9%, above the median of 1.16% for all subjects with asthma. (D) Subject with nonsevere asthma, P-selectin of 9.4 ng/ml, VWFpp of 107 U/dl, VWFpp/Ag of 1.23, and area of signal density on MDCT less than −950 HU at TLC of 0.25%, below the median of 1.16% for all subjects with asthma. Highlighted in yellow = regions of signal density less than −950 HU at TLC.
<i>Figure 2.</i>
Figure 2.
Secretory pathways of von Willebrand factor (VWF) and P-selectin from endothelial cells and proposed explanation for differential associations of VWF propeptide (VWFpp) and P-selectin with airway changes or defects in asthma. (A) VWF mature protein (VWF:Ag) and VWFpp are constitutively secreted into blood plasma and packaged together as a complex in tubular structures within Weibel-Palade granules, from which they are secreted in a regulated manner. P-selectin is a type I membrane protein sequestered in Weibel-Palade granules with its extracellular domain jutting into the granule. P-selectin becomes displayed on the endothelial cell surface when granules translocate to the surface on endothelial cell activation, and may be released subsequently into blood plasma by proteolysis. Endothelial cells of capillary cells lack Weibel-Palade granules and thus have only constitutive secretion of VWF and P-selectin. (B) Left, airway from subject with normal extent of vascularity and level of VWFpp secretion. Right, airway from subject with increased vascularity and high plasma VWFpp originating from the increased mass of endothelial cells. The increased vascularity reported by high VWFpp is thought to be associated with obstruction and ventilation defects in the larger and more central airways as detected by hyperpolarized helium-3 magnetic resonance imaging. (C) Left, normal terminal airspace and normal level of P-selectin secretion. Right, abnormal terminal airspace structure detected by multidetector computed tomography at TLC is associated with abnormal vasculature containing endothelial cells with increased synthesis and release of P-selectin into plasma. Green = VWF:Ag; purple = VWFpp; red = P-selectin. Based on present data and published information (, , , , , , , , –43, 65, 66, 70).
<i>Figure 3.</i>
Figure 3.
Correlations between imaging metrics and von Willebrand factor (VWF) or P-selectin in Severe Asthma Research Program subjects with asthma and receiver operating characteristic (ROC) curves for the ability of VWF and P-selectin to predict defect volume on hyperpolarized helium-3 magnetic resonance imaging (HPHe-MRI) and low-attenuation area on multidetector computed tomography (MDCT), respectively. (A and B) Percentage defect volume on HPHe-MRI versus plasma concentration of VWF propeptide (VWFpp) (A) or VWFpp/VWF mature protein (VWF:Ag) (B). (C) Percentage area of signal density on MDCT less than −950 HU at TLC versus plasma concentration of soluble P-selectin. (D) ROC curve for the ability of VWFpp to predict percentage defect volume on HPHe-MRI greater than 6%; area under curve (AUC) = 0.76, P = 0.007; for criterion greater than 131.6 U/dl, sensitivity = 70% and specificity = 82%. (E) ROC curve for the ability of VWFpp/Ag to predict percentage defect volume on HPHe-MRI greater than 8.25%, AUC = 0.78, P = 0.008; for criterion greater than 1.27, sensitivity = 80% and specificity = 73%. (F) ROC curve for the ability of P-selectin to predict percentage area of signal density of MDCT less than −950 HU greater than 0.8%; AUC = 0.71, P = 0.002; for criterion greater than 29 ng/ml, sensitivity = 46% and specificity = 91%. P = probability, rs = Spearman rank correlation coefficient. U = unit in which pooled normal plasma has 100 U/dl. Ratio was calculated from U/dl VWFpp divided by U/dl VWF:Ag.
<i>Figure 4.</i>
Figure 4.
Concentrations of von Willebrand factor propeptide (VWFpp), VWF mature protein (VWF:Ag), and P-selectin after whole-lung inhaled antigen challenge in subjects with mild allergic asthma. (A) VWFpp, (B) VWF:Ag, (C) VWFpp/Ag, and (D) P-selectin. Panels show individual values (left), means of absolute values (center), and means of values expressed as percentage of baseline (right). U = unit. **P less than or equal to 0.01 for increase versus baseline at 0 hours. n = 12.

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