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Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis
Yanyan Qu, … , Prabir Ray, Janet S. Lee
Yanyan Qu, … , Prabir Ray, Janet S. Lee
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e96914. https://doi.org/10.1172/jci.insight.96914.
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Research Article Pulmonology

Thrombospondin-1 protects against pathogen-induced lung injury by limiting extracellular matrix proteolysis

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Abstract

Acute lung injury is characterized by excessive extracellular matrix proteolysis and neutrophilic inflammation. A major risk factor for lung injury is bacterial pneumonia. However, host factors that protect against pathogen-induced and host-sustained proteolytic injury following infection are poorly understood. Pseudomonas aeruginosa (PA) is a major cause of nosocomial pneumonia and secretes proteases to amplify tissue injury. We show that thrombospondin-1 (TSP-1), a matricellular glycoprotein released during inflammation, dose-dependently inhibits PA metalloendoprotease LasB, a virulence factor. TSP-1–deficient (Thbs1–/–) mice show reduced survival, impaired host defense, and increased lung permeability with exaggerated neutrophil activation following acute intrapulmonary PA infection. Administration of TSP-1 from platelets corrects the impaired host defense and aberrant injury in Thbs1–/– mice. Although TSP-1 is cleaved into 2 fragments by PA, TSP-1 substantially inhibits Pseudomonas elastolytic activity. Administration of LasB inhibitor, genetic disabling of the PA type II secretion system, or functional deletion of LasB improves host defense and neutrophilic inflammation in mice. Moreover, TSP-1 provides an additional line of defense by directly subduing host-derived proteolysis, with dose-dependent inhibition of neutrophil elastase from airway neutrophils of mechanically ventilated critically ill patients. Thus, a host matricellular protein provides dual levels of protection against pathogen-initiated and host-sustained proteolytic injury following microbial trigger.

Authors

Yanyan Qu, Tolani Olonisakin, William Bain, Jill Zupetic, Rebecca Brown, Mei Hulver, Zeyu Xiong, Jesus Tejero, Robert M.Q. Shanks, Jennifer M. Bomberger, Vaughn S. Cooper, Michael E. Zegans, Hyunryul Ryu, Jongyoon Han, Joseph Pilewski, Anuradha Ray, Zhenyu Cheng, Prabir Ray, Janet S. Lee

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Figure 1

Thbs1–/– mice show enhanced mortality, failure to regain weight, higher lung bacterial burden, increased splenic dissemination, and increased airspace neutrophil recruitment and lung microvascular permeability following intratracheal Pseudomonas aeruginosa inoculation.

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Thbs1–/– mice show enhanced mortality, failure to regain weight, higher...
Thbs1–/– and WT mice were intratracheally instilled with P. aeruginosa (PA) at 106 inoculum. (A) Kaplan–Meier survival curve of WT and Thbs1–/– mice following i.t. infection with PA (n = 12 mice per group), *P < 0.05 by log-rank (Mantel-Cox) test. (B) Mice weights were measured for 8 days in WT and Thbs1–/– mice following i.t. infection with PA (n = 12 mice per group), *P < 0.05 by 2-way ANOVA with Sidak multiple comparisons. (C–H) In separate experiments, mice were sacrificed at a predetermined time point of 20 hours after infection and (C) lung CFU/ml, (D) spleen CFU/ml, (E) total bronchoalveolar lavage (BAL) cell counts/ml, (F) total BAL PMN counts/ml, (G) total BAL protein concentrations, and (H) BAL free neutrophil elastase (NE) activity were measured. (I) Representative H&E–stained sections of mouse lungs following i.t. PA inoculation. Each data point represents an individual mouse, with lines that indicate the median. The combined results of 2 independent experiments are shown in C–H. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed Mann-Whitney U test.

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