Phosphodiesterase-4 Inhibitor Roflumilast Attenuates Pulmonary Air Emboli-Induced Lung Injury.

Abstract

BACKGROUND:

Pulmonary air embolism (PAE)-induced acute lung injury (ALI) can be caused by massive air entry into the lung circulation. PAE can occur during diving, aviation, and some iatrogenic invasive procedures. PAE-induced ALI presents with severe inflammation, hypoxia, and pulmonary hypertension, and it is a serious complication resulting in significant morbidity and mortality. Phosphodiesterase-4 (PDE4) inhibitors can regulate inflammation and are therefore expected to have a therapeutic effect on ALI. However, the effect of the PDE4 inhibitor roflumilast on PAE-induced ALI is unknown.

METHODS:

The PAE model was undertaken in isolated-perfused rat lungs. Four groups (n = 6 in each group) were defined as follows: control, PAE, PAE + roflumilast 2.5 mg/kg, and PAE + roflumilast 5 mg/kg. Induction of PAE-induced ALI was achieved via the infusion of 0.7 cc air through the pulmonary artery. Roflumilast was administered via perfusate. All groups were assessed for pulmonary microvascular permeability, lung histopathology changes, pulmonary edema (lung weight/body weight, lung wet/dry weight ratio), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17, nuclear factor-kappa B (NF-κB), and inhibitor of NF-κB alpha (IκB-α).

RESULTS:

After the induction of air, PAE-induced ALI presented with pulmonary edema, pulmonary microvascular hyperpermeability, and lung inflammation with neutrophilic sequestration. The PAE-induced ALI also presented with increased expressions of IL-1β, IL-6, IL-8, IL-17, TNF-α, and NF-κB and decreased expression of IκB-α. The administration of roflumilast decreased pulmonary edema, inflammation, cytokines, NF-κB, and restored IκB-α level.

CONCLUSIONS:

PAE-induced ALI presents with lung inflammation with neutrophilic sequestration, pulmonary edema, hyperpermeability, increased cytokine levels, and activation of the NF-κB pathway. Roflumilast attenuates lung edema and inflammation and downregulates the NF-κB pathway and cytokines.

• Authors: Chung-Kan Peng, Kun-Lun Huang, Chin-Pyng Wu, Yao-Kuang Wu, I-Shiang Tzeng, Chou-Chin Lan
• Journal: The Journal of surgical research (J Surg Res) Vol. 241 Pg. 24-30 (09 2019) ISSN: 1095-8673 [Electronic] United States
• PMID: 31004869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Aminopyridines
• Benzamides
• Cyclopropanes
• Cytokines
• NF-kappa B
• Phosphodiesterase 4 Inhibitors
• Roflumilast

Topics

• Acute Lung Injury (diagnosis, drug therapy, etiology)
• Aminopyridines (administration & dosage)
• Animals
• Benzamides (administration & dosage)
• Capillary Permeability (drug effects)
• Cyclopropanes (administration & dosage)
• Cytokines (metabolism)
• Disease Models, Animal
• Embolism, Air (complications)
• Humans
• Lung (blood supply, drug effects, pathology)
• Male
• NF-kappa B (metabolism)
• Perfusion (methods)
• Phosphodiesterase 4 Inhibitors (administration & dosage)
• Rats
• Signal Transduction (drug effects)