Surfactant protein A and D polymorphisms and methylprednisolone pharmacogenetics in donor lungs

Beatrice Aramini; Patrick Geraghty; David J Lederer; Joseph Costa; Susan L DiAngelo; Joanna Floros; Frank D'Ovidio

doi:10.1016/j.jtcvs.2018.12.098

Surfactant protein A and D polymorphisms and methylprednisolone pharmacogenetics in donor lungs

J Thorac Cardiovasc Surg. 2019 May;157(5):2109-2117. doi: 10.1016/j.jtcvs.2018.12.098. Epub 2019 Jan 21.

Authors

Beatrice Aramini¹, Patrick Geraghty², David J Lederer¹, Joseph Costa¹, Susan L DiAngelo³, Joanna Floros³, Frank D'Ovidio⁴

Affiliations

¹ Division of Thoracic Surgery, Columbia University Medical Center, New York, NY.
² Division of Pulmonary and Critical Care Medicine, State University of New York Downstate Medical Center, Brooklyn, NY.
³ Center for Host defense, Inflammation, and Lung Disease (CHILD) Research Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, Pa.
⁴ Division of Thoracic Surgery, Columbia University Medical Center, New York, NY. Electronic address: fd2133@cumc.columbia.edu.

PMID: 30827536
DOI: 10.1016/j.jtcvs.2018.12.098

Abstract

Objective: Surfactant proteins A and D are important molecules involved in lung allograft innate immunity. Genetic polymorphisms of surfactant proteins A and D are associated with various lung diseases. In this study, surfactant protein A and D expression responses were investigated during pharmacogenetics upon methylprednisolone treatment as observed during lung transplantation.

Methods: A human cell line (NCI-H441) and precision-cut lung slices from 16 human donors were incubated with methylprednisolone, and surfactant protein A1, surfactant protein A2, and surfactant protein D messenger RNA and surfactant protein A protein expression were assayed. Surfactant protein A1, A2, and D polymorphisms and surfactant protein A gene and protein expressions were determined.

Results: In NCI-H441 cells, methylprednisolone treatment at 10^-5 M and 10^-6 M reduced surfactant protein A1 and surfactant protein A2 messenger RNA and surfactant protein A protein expression (P < .05). A pharmacogenetic relationship was observed in human donor precision-cut lung slices between the surfactant protein A2 (1A^x) variants: Surfactant protein A1, A2, and D messenger RNA expression were greater for 1A⁰ versus 1A¹ (P < .05); surfactant protein A1/surfactant protein A2 genotype 6A²6A²/1A⁰1A⁰ (n = 5) showed greater surfactant protein A1, A2, and D messenger RNA expression and surfactant protein A protein expression compared with the other surfactant protein A1/surfactant protein A2 genotypes (n = 11) (P < .05).

Conclusions: The surfactant protein A genotype and methylprednisolone stimuli influence donor lung surfactant protein A and D expression. Lungs carrying the surfactant protein A2 variant 1A⁰ have a greater expression of surfactant protein A when treated with methylprednisolone. Surfactant protein A polymorphisms could be used to personalize immunosuppressive regimens.

Keywords: lung transplant; methylprednisolone polymorphism; pharmacogenetics; surfactant protein A and D.

MeSH terms

Cell Line
Dose-Response Relationship, Drug
Gene Expression Regulation
Gene Frequency
Genotype
Glucocorticoids / pharmacology*
Humans
Immunosuppressive Agents / pharmacology*
In Vitro Techniques
Lung / drug effects*
Lung / metabolism
Lung Transplantation*
Methylprednisolone / pharmacology*
Pharmacogenomic Variants*
Polymorphism, Genetic*
Pulmonary Surfactant-Associated Protein A / genetics*
Pulmonary Surfactant-Associated Protein A / metabolism
Pulmonary Surfactant-Associated Protein D / genetics*
Pulmonary Surfactant-Associated Protein D / metabolism
Tissue Donors*

Substances

Glucocorticoids
Immunosuppressive Agents
Pulmonary Surfactant-Associated Protein A
Pulmonary Surfactant-Associated Protein D
SFTPA1 protein, human
SFTPA2 protein, human
Methylprednisolone