Inhalation of an endothelin receptor A antagonist attenuates pulmonary inflammation in experimental acute lung injury.

Abstract

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg.kg(-1), ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in PaO2 (316 +/- 47 mm Hg vs. control 53 +/- 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% +/- 1% positive cells vs. control 12% +/- 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 +/- 1 pg.100 mg-1 wet weight vs. control 7 +/- 1 pg.100 mg(-1) wet weight, p < 0.05). Concentrations of TNF-alpha, IL-1beta, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.

• Authors: Philipp Kalk, Philine Senf, Maria Deja, Bodil Petersen, Thilo Busch, Christian Bauer, Willehad Boemke, Udo Kaisers, Berthold Hocher
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 86 Issue 8 Pg. 511-5 (Aug 2008) ISSN: 0008-4212 [Print] Canada
• PMID: 18758498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endothelin A Receptor Antagonists
• Endothelin-1
• Immunologic Factors
• Interleukin-1
• Phenylpropionates
• Pyrimidines
• Tumor Necrosis Factor-alpha
• darusentan
• Oxygen

Topics

• Administration, Inhalation
• Animals
• Blood Pressure (drug effects)
• Cytokines (metabolism)
• Data Interpretation, Statistical
• Endothelin A Receptor Antagonists
• Endothelin-1 (metabolism)
• Heart Rate (drug effects)
• Immunoenzyme Techniques
• Immunologic Factors (administration & dosage, therapeutic use)
• Interleukin-1 (metabolism)
• Lung (immunology, pathology)
• Oxygen (blood)
• Phenylpropionates (administration & dosage, therapeutic use)
• Pneumonia (chemically induced, drug therapy, immunology)
• Pulmonary Circulation (drug effects)
• Pulmonary Gas Exchange (drug effects)
• Pyrimidines (administration & dosage, therapeutic use)
• Swine
• Tumor Necrosis Factor-alpha (metabolism)