The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung
Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A. Matthay
Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A. Matthay
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Research Article Infectious disease Pulmonology Therapeutics

The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung

Abstract

Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection. This study tested these potential therapeutic mechanisms of the TIP peptide in a clinically relevant preparation of the ex vivo–perfused human lung injured by Streptococcus pneumoniae. Therapeutic administration of the TIP peptide reduced pulmonary barrier permeability to protein and lung edema formation, increased alveolar edema fluid clearance, and produced an antiinflammatory effect in the airspaces with reductions in IL-6 and IL-8 levels. Additionally, the TIP peptide reduced the translocation of bacteria into the circulation. These findings establish 3 mechanisms of benefit with the TIP peptide to reduce injury in the human lung and support the clinical relevance as a potential therapeutic for pneumococcal bacterial pneumonia.

Authors

Mazharul Maishan, Hiroki Taenaka, Bruno Evrard, Shotaro Matsumoto, Angelika Ringor, Carolyn Leroux, Rudolf Lucas, Michael A. Matthay

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Figure 1

A translational model of bacterial pneumonia using the ex vivo–perfused human lung injured by S. pneumoniae.

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A translational model of bacterial pneumonia using the ex vivo–perfused ...
(A) Schematic showing the human lung perfusion preparation. Either the right or the left lung from a donor not accepted for transplant was selected for perfusion based on the absence of injury by gross appearance. A perfusate mixture of physiological medium and fresh whole blood was circulated by a roller pump through the cannulated pulmonary artery (PA) and drained freely out of the pulmonary vein (PV). Once warmed to 37°C, the lung was inflated with 8 cmH2O of continuous positive airway pressure (CPAP) through an endobronchial tube secured to the main bronchus. (B–E) Photographs of representative human lungs that were perfused ex vivo and inflated with CPAP. The 2 photographs on the left show a human lung, immediately after inflation at the beginning of the experiment (B) and after 6 hours of perfusion (C), from the control group, which did not receive bacteria but only saline vehicle (white circle). The 2 photographs on the right show a human lung from a different donor immediately after inflating (D), instilled with 5 × 1010 colony-forming units (CFU) of S. pneumoniae after 1.5 hours, and perfused for a total of 6 hours (E), resulting in visible infiltrates in the region where bacteria were instilled (white circle) and spreading of injury through the lower lobe (gray circle). (F) Experimental timeline for ex vivo human lung perfusion studies with measurements of AFC in a separate set of experiments to test the effect of the TIP peptide targeting the ENaC. After inflating the lung, AFC was measured, and the perfusion experiment was continued if this initial AFC was greater than 20% per hour to ensure the donor lung had relatively normal AFC function at baseline.