A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures

Mohamad H Tiba^{1

2}, Brendan M McCracken^{1

2}, Danielle C Leander^{1

2}, Carmen I Colmenero^{1

2}, Jean A Nemzek^{2

3}, Michael W Sjoding^{2

4

5

6}, Kristine E Konopka^{2

7}, Thomas L Flott^{2

8}, J Scott VanEpps^{1

2

9

10}, Rodney C Daniels^{2

9

11}, Kevin R Ward^{1

2

9}, Kathleen A Stringer^{2

4

8}, Robert P Dickson^{2

4

12}

Affiliations

¹ Department of Emergency Medicine, University of Michigan, Ann Arbor, MI, USA.
² Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, USA.
³ Unit of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁵ Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Pediatrics, Pediatric Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, USA.

PMID: 33991456
PMCID: PMC8123544
DOI: 10.14814/phy2.14871

A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures

Mohamad H Tiba et al. Physiol Rep. 2021 May.

. 2021 May;9(9):e14871.

doi: 10.14814/phy2.14871.

Authors

Affiliations

¹ Department of Emergency Medicine, University of Michigan, Ann Arbor, MI, USA.
² Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, USA.
³ Unit of Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁵ Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Pediatrics, Pediatric Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
¹² Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, USA.

PMID: 33991456
PMCID: PMC8123544
DOI: 10.14814/phy2.14871

Abstract

To date, existing animal models of the acute respiratory distress syndrome (ARDS) have failed to translate preclinical discoveries into effective pharmacotherapy or diagnostic biomarkers. To address this translational gap, we developed a high-fidelity swine model of ARDS utilizing clinically relevant lung injury exposures. Fourteen male swine were anesthetized, mechanically ventilated, and surgically instrumented for hemodynamic monitoring, blood, and tissue sampling. Animals were allocated to one of three groups: (1) Indirect lung injury only: animals were inoculated by direct injection of Escherichia coli into the kidney parenchyma, provoking systemic inflammation and distributive shock physiology; (2) Direct lung injury only: animals received volutrauma, hyperoxia, and bronchoscope-delivered gastric particles; (3) Combined indirect and direct lung injury: animals were administered both above-described indirect and direct lung injury exposures. Animals were monitored for up to 12 h, with serial collection of physiologic data, blood samples, and radiographic imaging. Lung tissue was acquired postmortem for pathological examination. In contrast to indirect lung injury only and direct lung injury only groups, animals in the combined indirect and direct lung injury group exhibited all of the physiological, radiographic, and histopathologic hallmarks of human ARDS: impaired gas exchange (mean PaO₂ /FiO₂ ratio 124.8 ± 63.8), diffuse bilateral opacities on chest radiographs, and extensive pathologic evidence of diffuse alveolar damage. Our novel porcine model of ARDS, built on clinically relevant lung injury exposures, faithfully recapitulates the physiologic, radiographic, and histopathologic features of human ARDS and fills a crucial gap in the translational study of human lung injury.

Keywords: acute lung injury; acute respiratory distress syndrome; critical care; diffuse alveolar damage; direct lung injury; indirect lung injury; porcine models; sepsis; septic shock.

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Figures

**FIGURE 1**
Comparison of oxygenation across experimental groups. Healthy Yorkshire‐mix swine, 14–16 weeks of age, were exposed to (1) *indirect lung injury* (*Escherichia coli* sepsis), (2) *direct lung injury* (hyperoxia, volutrauma, and aspiration of gastric particles), and (3) *combined direct and indirect lung injury* (all above exposures). Group 1 versus Group 3: p = 0.02. Group 2 versus Group 3: p = 0.03. Lines and variance represent means and standard deviation, both with Lowess smoothing. Significance determined using ANOVA with the Holm–Šidák correction for multiple comparisons

**FIGURE 2**
Representative chest radiographs across experimental groups. Ventral‐dorsal chest radiographs were obtained at baseline and every 4 h following exposure for the duration of the experiment. Images were scored by two Pulmonary & Critical Care Medicine physicians (blinded to experimental group and timepoint) using a scale from 1 (normal) to 10 (severe, diffuse bilateral opacities). The mean chest radiograph score across two reviewers is reported. Interobserver correlation was high (Pearson r = 0.94)

**FIGURE 3**
Representative histopathology across experimental groups. Post‐mortem lung tissue was examined by an expert thoracic pathologist using a semi‐quantitative instrument for identifying key features of diffuse alveolar damage (DAD). (a) Of the four animals examined in Group 1 (*indirect lung injury only*), three were graded as *normal*. Abnormal findings included mildly increased interstitial cellularity and focal acute pneumonia in a single animal. No animals in Group 1 exhibited features of DAD. (b) Of the four animals examined in Group 2 (*direct lung injury only*), all four exhibited features of acute bronchopneumonia with intra‐alveolar edema. No animals in Group 2 exhibited features of DAD. (c) Of the five animals examined in Group 3 (*combined indirect and direct lung injury*), 4/5 were classified as *definite DAD*. Prominent findings in Group 3 included hyaline membranes (4/5), intra‐alveolar edema (3/5), fibrin thrombi (5/5) and acute bronchopneumonia (5/5)

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A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures

Affiliations

A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Miscellaneous