Urokinase plasminogen activator receptor-deficient mice demonstrate reduced hyperoxia-induced lung injury.
Patients with respiratory failure often require supplemental oxygen therapy and mechanical ventilation. Although both supportive measures are necessary to guarantee adequate oxygen uptake, they can also cause or worsen lung inflammation and injury. Hyperoxia-induced lung injury is characterized by neutrophil infiltration into the lungs. The urokinase plasminogen activator receptor (uPAR) has been deemed important for leukocyte trafficking. To determine the expression and function of neutrophil uPAR during hyperoxia-induced lung injury, uPAR expression was determined on pulmonary neutrophils of mice exposed to hyperoxia. Hyperoxia exposure (O2>80%) for 4 days elicited a pulmonary inflammatory response as reflected by a profound rise in the number of neutrophils that were recovered from bronchoalveolar lavage fluid and lung cell suspensions, as well as increased bronchoalveolar keratinocyte-derived chemokine, interleukin-6, total protein, and alkaline phosphatase levels. In addition, hyperoxia induced the migration of uPAR-positive granulocytes into lungs from wild-type mice compared with healthy control mice (exposed to room air). uPAR deficiency was associated with diminished neutrophil influx into both lung tissues and bronchoalveolar spaces, which was accompanied by a strong reduction in lung injury. Furthermore, in uPAR(-/-) mice, activation of coagulation was diminished. These data suggest that uPAR plays a detrimental role in hyperoxia-induced lung injury and that uPAR deficiency is associated with diminished neutrophil influx into both lung tissues and bronchoalveolar spaces, accompanied by decreased pulmonary injury.
Center for Experimental and Molecular Medicine (CEMM), G2-130, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam. M.A.vanZoelen@amc.uva.nl
Marieke A D
MA
van Zoelen
Sandrine
S
Florquin
Regina
R
de Beer
Jennie M
JM
Pater
Marleen I
MI
Verstege
Joost C M
JC
Meijers
Tom
T
van der Poll
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018496:Hyperoxia / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis; D055370:Lung Injury / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis* / Q000172:deficiency
D018925:Chemokines; D015850:Interleukin-6; D055293:Receptors, Urokinase Plasminogen Activator; C074302:keratinocyte-derived chemokines