Extracellular nucleic acid as DAMPs in severe pneumonia: therapeutic intervention with adrenomedullin

Introduction:

Pneumonia remains a significant health burden worldwide and despite adequate antibiotic treatment, mortality rates range up to 23% of the affected patients. The gram-positive bacteria Streptococcus pneumoniae is the main pathogen causing these infections. A dysregulated immune response might be the cause for lung injury and the associated systemic sequelae. Endogenous extracellular nucleic acids may act as “Danger-associated molecular pattern” (DAMP), being directly involved in this immunological disorder. eRNA, released under pathological conditions, acts as a pro-inflammatory and permeability-increasing mediator, and NETs are relevant for trapping and killing microbes, but also promoting cytotoxicity and microvascular thrombosis.

Objectives:

Aim of the study is to characterize the generation and role of these DAMPs in pneumonia and to evaluate the endogenous peptide adrenomedullin (ADM) as therapeutic agent for pulmonary barrier stabilization and prevention of extra-pulmonary organ dysfunction.

Results:

Using an in vivo mouse model of pneumonia adapted to the life-saving strategy of mechanical ventilation, ADM administration revealed protective functions by significantly decreasing lung edema, pulmonary and extra-pulmonary organ damage and preventing microcirculatory coagulopathy, without interfering with the inflammatory response. The generation of eRNA and NETs, increased upon infection, was significantly reduced in bronchoalveolar lavage upon treatment with ADM. Furthermore, ADM reduced NET-formation in vitro in isolated neutrophils, demonstrated by immunohistochemistry and ELISA and probably by regulating the respiratory burst.

Conclusion:

ADM may rescue endothelial barrier integrity by increasing intracellular cAMP levels, which influence ROS production, necessary in NETosis. The results here show that ADM significantly affects the release of extracellular nucleic acids, indicating a protective role in lung damage during S. pneumonia infection.

Erratum: P456 The list of authors has been changed to
Teixeira Alves LG¹, Wienhold SM¹, Fischer S², Suttorp N¹, Witzenrath M¹, Müller-Redetzky H¹
1 Department of Internal Medicine, Infectious Disease and Respiratory
Medicine, Charité-Universitätsmedizin Berlin; 2 Institute for Biochemistry,
Justus-Liebig University