PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils
Dongyan Song, Jose M. Adrover, Christy Felice, Lisa N. Christensen, Xue-Yan He, Joseph R. Merrill, John E. Wilkinson, Tobias Janowitz, Scott K. Lyons, Mikala Egeblad, Nicholas K. Tonks
Dongyan Song, Jose M. Adrover, Christy Felice, Lisa N. Christensen, Xue-Yan He, Joseph R. Merrill, John E. Wilkinson, Tobias Janowitz, Scott K. Lyons, Mikala Egeblad, Nicholas K. Tonks
View: Text | PDF
Research Article Cell biology

PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils

Abstract

Acute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti–MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture–induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies.

Authors

Dongyan Song, Jose M. Adrover, Christy Felice, Lisa N. Christensen, Xue-Yan He, Joseph R. Merrill, John E. Wilkinson, Tobias Janowitz, Scott K. Lyons, Mikala Egeblad, Nicholas K. Tonks

×

Figure 1

PTP1B inhibitors improved survival and ameliorated lung damage in the TRALI mouse model.

Options: View larger image (or click on image) Download as PowerPoint
PTP1B inhibitors improved survival and ameliorated lung damage in the TR...
(A) Schematic illustration of the TRALI induction and PTP1B inhibition protocol. (B) The survival curves of TRALI mice treated with increasing concentrations of the PTP1B inhibitor MSI-1436 or saline (n = 20 mice, 2 independent biological repeats). (C) The survival curves of TRALI mice treated with increasing concentrations of the PTP1B inhibitor DPM-1003 or saline (n = 20–25 mice, 2 independent biological repeats). (D) Representative images of H&E-stained lung tissue from no treatment mice (NT), and TRALI mice after administering saline, MSI-1436 at 2 mg/kg, or MSI-1436 at 10 mg/kg. Arrows indicate alveolar damage. Asterisks indicate edema or hyaline membranes. Scale bars: 25 μm. Lung injury scores for each treatment group. (n = 4 mice per group). (E) The protein concentrations in the bronchoalveolar lavage fluid (BALF) collected from NT or TRALI mice treated with either saline or 10 mg/kg MSI-1436 (n = 6 mice per group). (F) Representative 3D-rendered images of lung volumes from CT scans of mice from the saline- and MSI-1436–treated TRALI mice. Cyan represents hyperdense areas of edema and vasculature (Hounsfield units [HU] > 0); gray represents hypodense regions of airspace — i.e. viable lung (HU < 0). (G) The percentage of viable lung volume (volume of viable lung/volume of total lung) calculated from longitudinal CT scans in 2 experimental groups as in F. (n = 7–8 mice per group). (H) The survival curves of CLP-induced sepsis model treated either with saline or 5 mg/kg MSI-1436 at 2 hours before surgery (n = 18 mice per group). Data are presented as mean ± SEM. Statistical analysis for B, C, and H by was done log-rank (Mantel-Cox) test; by nonparametric 2-tailed Mann-Whitney test for D; by 1-way ANOVA with Tukey’s multiple-comparison test for E; and by 2-way ANOVA for G. *P < 0.05, **P < 0.01, ****P < 0.0001