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Spatial Heterogeneity of Lung Strain and Aeration and Regional Inflammation During Early Lung Injury Assessed with PET/CT

Posted Feb 28, 2019 Updated Apr 10, 2023
By Gabriel Motta-Ribeiro MSc , Tilo Winkler PhD , Soshi Hashimoto , Marcos F. Vidal Melo MD PhD
16 min read

Introduction

Spatial heterogeneity of lung aeration and strain (change volume/resting volume) occurs at microscopic levels and contributes to lung injury. Yet, it is mostly assessed with histograms or large regions-of-interest. Spatial heterogeneity could also influence regional gene expression. We used positron emission tomography (PET)/computed tomography (CT) to assess the contribution of different length-scales to mechanical heterogeneity and to direct lung injury biological pathway identification.

Materials and Methods

Sheep exposed to mild ( n = 5, supine and n = 3, prone) and moderate ( n = 6, supine) systemic endotoxemia were protectively ventilated. At baseline, 6 hours and 20 hours length-scale analysis was applied to aeration in CT (mild groups) and PET transmission (moderate group) scans; and voxel-level strain derived from image registration of end-inspiratory and end-expiratory CTs (mild). 2-deoxy-2-[(18)F]fluoro-d-glucose ( 18 F-FDG)-PET kinetics parameters in ventral and dorsal regions were correlated with tissue microarray gene expression (moderate).

Results

While aeration and strain heterogeneity were highest at 5–10 mm length-scales, larger length-scales contained a higher fraction of strain than aeration heterogeneity. Contributions of length-scales >5–10 mm to aeration and strain heterogeneity increased as lung injury progressed ( p < 0.001) and were higher in supine than prone animals. Genes expressed with regional correlation to 18 F-FDG-PET kinetics (|r| = 0.81 [0.78–0.85]) yielded pathways associated with immune system activation and fluid clearance.

Conclusion

Normal spatial heterogeneity of aeration and strain suggest larger anatomical and functional determinants of lung strain than aeration heterogeneity. Lung injury and supine position increase the contribution of larger length-scales. 18 F − FDG-PET-based categorization of gene expression results in known and novel biological pathways relevant to lung injury.

Introduction

Excessive mechanical forces can produce lung injury during mechanical ventilation. Indeed, regional strain (change in lung volume/resting lung volume) has been shown to relate to local lung inflammation particularly in the presence of systemic inflammation ( ). Excessive mechanical forces can occur not only at large lung areas of hyperinflation ( ) but also at the microscopic level. Experiments utilizing total lung capacity maneuvers in excised dog lobes revealed heterogeneity of regional gas volume changes in relation to gas volume at total lung capacity at length-scales as small as ∼2 mm ( ). In fact, pressure–volume relationships determining lung expansion are related to properties that scale down to the microscopic level of collagen and elastin fibers ( ). A theoretical study indicated that mechanical stress is significantly amplified around collapsed alveoli ( ). Despite the relevance of such small length-scale phenomena, most studies on pulmonary static and dynamic strain are based on whole lung ( ) or large regions-of-interest (ROI) ( ). Given that heterogeneity of lung expansion is relevant to lung injury, it is important to understand its topographic basis. Yet, information is scant on the length-scales contributing to strain and aeration heterogeneity during mechanical ventilation. Computed tomography (CT) imaging and elastic registration allow for estimation of a range of such length-scale contribution by assessment of in vivo regional tissue strain and aeration.

Lung injury results from complex interactions among mechanical and biological factors ( ). The inflammatory response to local and global stimuli includes recruitment of cells such as neutrophils and affects pulmonary regional metabolic activity, allowing for its in vivo assessment with the positron emission tomography (PET) tracer 2-deoxy-2-[(18)F]fluoro-d-glucose ( 18 F-FDG) ( ). Recently, we showed that 18 F-FDG-PET could provide an early imaging biomarker for acute respiratory distress syndrome (ARDS) before this condition is clinically established, as well as guide tissue sampling for gene expression analysis ( ). Of note, 18 F-FDG-PET kinetics allows for estimation of parameters characterizing tissue phosphorylation rate, associated with tumor aggressiveness and response to therapy in oncological studies ( ) and with cytokine gene expression in experimental acute lung injury (ALI) ( ). Accordingly, 18 F-FDG-PET kinetics parameters could be a promising tool to guide the analysis of gene expression datasets and identify pathways relevant to the mechanism and treatment of ALI.

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Materials and Methods

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Experimental Protocol

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Moderate Endotoxemia

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Transcriptome-wide gene expression analysis

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Mild Endotoxemia

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Imaging protocol

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Strain estimation

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Image noise estimation

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Selection of Voxels for Analysis

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Aeration Levels

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Length-scale Analysis

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Statistical Analysis

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Results

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Figure 1, Lung aeration in sheep mechanically ventilated with low tidal volume and low to moderate positive and-expiratory pressure for 20–24 hours. After the first measurement, intravenous infusion of Lipopolysaccharide was started to generate moderate (10 ng/kg/min) or mild (2.5 ng/kg/min) systemic endotoxemia. Aeration was quantified as the gas fraction (F GAS ) in each voxel of transmission (moderate group) and computed tomography (mild groups) scans during tidal ventilation. (a) Non- (black), poorly- (dark grey), normally- (light grey), and hyper-aerated (white) compartments are expressed as a fraction of total lung mass. Irrespective of the endotoxin dose, nonaerated regions increased after 20 hours in supine, but not in prone animals. For supine sheep, the spatial distribution of aeration followed a gravitational gradient decreasing toward dorsal regions. (b) Aeration level at 24 hours * vs 0 hour and & vs 6 hours for the same group; ^ vs moderate and # vs mild-prone for the same aeration compartment; one symbol p < 0.05, two symbols p < 0.001.

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Length-scales of Aeration Heterogeneity

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Figure 2, Contribution of length-scale ranges to lung aeration heterogeneity. Sheep with moderate (a, 10 ng/kg/min LPS) or mild (b, c, 2.5 ng/kg/min LPS) endotoxemia were mechanically ventilated using low tidal volume and low to moderate positive end-expiratory pressure. The contribution of a length-scale range was assessed by the difference between the variances normalized by the square mean in mean lung volume images filtered for effective resolutions from 13 to 91 mm. Values were expressed relative to the smallest length-scale (13–26 mm). In both endotoxemia levels and body positions (supine, a and c, prone, b), the largest contribution to heterogeneity was in the length-scale 13–26 mm, with an increase in the contribution of larger length-scales along time. Contribution of larger length-scales decreased with the mean gas fraction (d).* p < 0.05, ** p < 0.01 and *** p < 0.001 for differences between consecutive length-scales.

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Figure 3, Contribution of length-scale ranges to lung aeration heterogeneity for mildly endotoxemic sheep in prone (left) and supine (rigth) positions. Animals were mechanically ventilated with low tidal volume and low positive end-expiratory pressure for 24 hours. The contribution of a length-scale range was assessed by the difference between the variances normalized by the square mean in images filtered for effective resolutions from 5 to 90 mm. Values were expressed relative to the smallest length-scale (5–10 mm). While both body positions displayed their largest contribution to heterogeneity in length-scale 5–10 mm, supine animals (right) showed substantially higher contribution of larger length-scales than prone (left). ** p < 0.01 and *** p < 0.001 for differences between consecutive length-scales.

Table 1

Noise level estimate in the full resolution mean lung volume CT converted to F GAS and the SD of voxels inside the lung mask after removing the gravitational gradient and filtering with 5 mm kernel

0 hour 6 hours 24 hours_p_ valuesIkeda et al. ( ) 0.021 ± 0.002 0.021 ± 0.002 0.021 ± 0.003 Time = 0.376Christianson et al. ( ) 0.027 ± 0.003 0.026 ± 0.003 0.025 ± 0.003 Method <0.001SD within lungsupine 0.094 ± 0.016 0.095 ± 0.013 0.127 ± 0.019 –prone 0.069 ± 0.001 0.066 ± 0.005 0.078 ± 0.009

CT, computed tomography; Fgas, gas fraction; SD, standard deviation.

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Length-scales of Tidal Strain Heterogeneity

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Figure 4, Contribution of length-scale ranges to lung tidal strain heterogeneity for mildly endotoxemic sheep in prone (left) or supine (right) positions. Animals were mechanically ventilated with low tidal volume and low positive end-expiratory pressure for 24 hours. The contribution of a length-scale was assessed by the difference between the variances normalized by the square mean in images filtered for effective resolutions from 5 to 90 mm. Values were expressed relative to the smallest length-scale (5–10 mm). Supine had higher relative contributions of all length-scales and showed significant change at 6 and 24 hours. Prone had no difference between time points. * p < 0.05, ** p < 0.01, and ** p < 0.001 for differences between consecutive length-scales. Strain was calculated with an initial B-spline knot distance of 26 mm.

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Figure 5, Distance between landmark points matched in the expiratory and inspiratory images before and after image registration using different distances for the knots of the B-spline regularization (13, 26, 52, and 130 mm). Landmark distance was used as a measure of overall image registration accuracy. Data correspond to two randomly selected supine sheep (S1 and S2) at the beginning (0 hour) and end of the experiment (24 hours). These time points were chosen because they represent the extremes in aeration and atelectasis. A measurement at 6 hours of a third sheep (S3) was added because it represented the study with the largest gas volume difference between inspiratory and expiratory images. An average of 95.8 points [range 74–122] were used for each animal-time point combination. Landmarks were semi-automatically matched in each pair of images by one observer. Dotted line represents the largest dimension of image voxels (2.5 mm). The B-spline knots’ distance corresponds to the first stage of registration.

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Figure 6, Contribution of length-scale ranges to lung tidal strain heterogeneity. Mildly endotoxemic (2.5 ng/kg/min LPS) supine sheep were mechanically ventilated using low tidal volume and low positive end-expiratory pressure. Voxel level strain was estimated using different distances between the knots of the B-spline regularization (13, 26, 52, and 130 mm in the first step). The contribution of a length-scale was assessed by the difference between the variances normalized by the squared mean in images filtered for effective resolutions from 5 to 35 mm. Values are normalized to the 5–10 mm. Only the baseline data was analyzed, as it was the time point with best agreement in landmarks distance between the four regularization factors. (a) Examples of the spatial distribution of strain estimated with each B-spline knots’ distance. Note the increase in size of the regions with similar colors from the upper (13 mm) to the lower (130 mm) images. (b) There was no qualitative difference in contributions of length-scales between 13, 26, and 52 mm. (c) Contribution of length-scale ranges at 0 hour and 24 hours for the largest knots’ distance showing a significant increase in contribution of length-scales larger than 30 mm after 24 hours. ** p < 0.01 and *** p < 0.001 for differences between consecutive length-scales. LPS, Lipopolysaccharide.

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Regional Phosphorylation Rates and Gene-expression

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Figure 7, Dorsal/ventral ratio of 18 F-FDG kinetic parameters and tissue fraction in sheep undergoing low tidal volume and low to moderate positive end-expiratory pressure mechanical ventilation, and moderate endotoxemia (10 ng/kg/min LPS). The phosphorylation rate and tissue-specific 18 F-FDG uptake rate at 6 hours were significantly different from 20 hours (# p < 0.05 and ## p < 0.01) indicating that dorsal and ventral regions started and ended with similar levels, but followed different temporal trajectories. This could indicate different biological process due to differences in aeration, tidal strain, ventilation, and perfusion. Tissue fraction increased at dorsal regions at 20 hours compared to both 6 and 0 hours (# and & p < 0.05).

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Table 2

Significant pathways amongst the genes that were correlated to 18 F-FDG kinetics parameters and tissue fraction. A pathway was considered significant if at least two of its’ genes were on the analyzed list and had EASE<0.1

Parameter Group Specific pathwaysTissue-specific uptake rate (Kis)Metabolism Fructose and mannose metabolism, Biosynthesis of antibioticsTissue specific volume of distribution (Fes)Environmental information processing PI3K-Akt signaling, Calcium signaling, NF-kappa B signaling, Jak-STAT signaling, TNF signaling, Cytokine-cytokine receptor interactionImmune system Toll-like receptor signaling, T cell receptor signaling, Natural killer cell mediated cytotoxicity, Antigen processing and presentationPhosphorylation rate (k 3 )Excretory system Aldosterone-regulated sodium reabsorptionTissue fraction (F TIS )Environmental information processing Jak-STAT signaling, Neuroactive ligand-receptor interactionImmune system Toll-like receptor signaling, T cell receptor signaling, RIG-I-like receptor signaling, Hematopoietic cell lineage

FDG, fluoro-d-glucose.

Table A.1

Complementary significant pathways amongst the genes that were correlated to the tissue-specific 18F-FDG volume of distribution and the tissue fraction. A pathway was considered significant if at least two of its’ genes were on the analyzed list and had an EASE <0.1.

Parameter Group PathwaysTissue specific volume of distribution (Fes)Diseases Alzheimer’s disease, Huntington’s disease, Salmonella infection, Pertussis, Legionellosis, Leishmaniasis, Chagas’ disease, African trypanosomiasis, Malaria, Toxoplasmosis, Amoebiasis, Tuberculosis, Hepatitis B, Measles, Influenza A, HTLV-1 infection, Herpes simplex infection, Proteoglycans cancer, Asthma, Inflammatory bowel disease, Rheumatoid arthritis, Allograft rejection, Graft-versus-host disease, Type I diabetes mellitus, Nonalcoholic fatty liver diseaseOther systems Prolactin signaling, Osteoclast differentiationTissue fraction (Ftiss)Diseases Salmonella infection, Pertussis, Leishmaniasis, Chagas’ disease, Influenza A, Pathways in cancerNervous system Long-term depression

FDG, fluoro-d-glucose.

Figure 8, Correlations between dorsal to ventral ratios of selected genes expression and 18 F-FDG kinetic parameters. The transport rate from the nonmetabolized to the metabolized compartment (k 3 ), which represents the phosphorylation of 18 F-FDG, was correlated with gene expression of hexokinase (HK1). The 18 F-FDG volume of distribution normalized by tissue fraction (Fes) is normally attributed to the number of neutrophils in the analyzed region and was correlated with the expression of toll-like receptors 2 and 4 (TLR2 and TLR4), which are involved in the process of neutrophil migration and bacteria detection.

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Discussion

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Methodological Considerations

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Figure A.1, Example of length-scale analysis with the multiple low-pass filter technique applied to check board patterns. All check boards have the same dimensions and total heterogeneity with size of white and black squares increasing from top to bottom.

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Length-scale Analysis of Aeration and Tidal Strain Heterogeneity

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Gene Expression Analysis

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Limitations

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Conclusion

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Acknowledgments

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Appendix

Simulated Example of Length-Scales

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Academic Radiology, Volume 26, Issue 3
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