Online Laboratory Investigations

Effect of Local Tidal Lung Strain on Inflammation in Normal and Lipopolysaccharide-Exposed Sheep*

Wellman, Tyler J. PhD^1,2; Winkler, Tilo PhD²; Costa, Eduardo L. V. MD, PhD²; Musch, Guido MD²; Harris, R. Scott MD³; Zheng, Hui PhD⁴; Venegas, Jose G. PhD²; Vidal Melo, Marcos F. MD, PhD²

Author Information

¹Department of Biomedical Engineering, Boston University, Boston, MA.

²Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

³Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

⁴Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

* See also p. 1745.

This work was performed at the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported by grants R01-HL086827 and R01-HL121228 from the National Heart, Lung, and Blood Institute.

Dr. Wellman received support for article research from the National Institutes of Health (NIH). Dr. Winkler has a patent and received support for article research from the NIH. Dr. Musch received support for article research from the NIH. His institution received grant support from the NIH (R01HL094639). Dr. Venegas received support for article research from the NIH. His institution received grant support. Dr. Vidal Melo has a patent and received support for article research from the NIH. His institution received grant support from the NIH (RO1 grant as listed in the article). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 42(7):p e491-e500, July 2014. | DOI: 10.1097/CCM.0000000000000346

Abstract

Objectives:

Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia.

Design:

Interventional animal study.

Setting:

Experimental laboratory and PET facility.

Subjects:

Eighteen 2- to 4-month-old sheep.

Interventions:

Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30–32 cm H₂O) with high-strain (V_T = 18.2 ± 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (V_T = 18.4 ± 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (V_T = 8.1 ± 0.2 mL/kg, positive end-expiratory pressure = 17 ± 3 cm H₂O). At baseline, we acquired respiratory-gated PET scans of inhaled ¹³NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [¹⁸F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest.

Measurements and Main Results:

Baseline regional tidal strain had a significant effect on [¹⁸F]fluoro-2-deoxy-D-glucose net uptake rate K_i in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k₃ in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k₃-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 ± 0.17) than high-strain (1.21 ± 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 ± 0.44; p < 0.001) and lower k₃ (p < 0.001) and K_i (p < 0.05) than high-strain lipopolysaccharide.

Conclusions:

Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [¹⁸F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [¹⁸F]fluoro-2-deoxy-D-glucose phosphorylation.