The Ron receptor tyrosine kinase regulates acute lung injury and suppresses nuclear factor kappaB activation.
Emerging information implies that the Ron receptor tyrosine kinase may play a role in the inflammatory response. However, the manner in which this receptor contributes to the response is not well understood. In the present studies, we investigated the role of the Ron receptor in the acute lung inflammatory response. Wild-type and mutant mice lacking the tyrosine kinase domain of Ron (Ron TK-/-) were subjected to acute lung injury induced by intranasal administration of bacterial lipopolysaccharide (LPS). Wild-type mice showed increased lung injury after LPS administration, as determined by the leakage of albumin into the lung and by histopathological changes. Ron TK-/- mice had more than twice the amount of albumin leak and much greater thickening of the alveolar septae. Lipopolysaccharide administration caused neutrophil recruitment into the lungs, as measured by myeloperoxidase. However, Ron TK-/- mice had much higher baseline levels of myeloperoxidase, which did not increase further after LPS. Lung injury in wild-type mice occurred with activation of the transcription factor, nuclear factor kappaB (NF-kappaB), and subsequent increases in intrapulmonary generation of tumor necrosis factor alpha. In TK-/- mice, there was far less IkappaB-alpha and IkappaB-beta protein and greater activation of NF-kappaB. This was associated with substantially increased production of tumor necrosis factor alpha and the nitric oxide (NO) by-product, nitrite. The data suggest that the Ron receptor tyrosine kinase plays an important regulatory role in acute inflammatory lung injury by suppressing signals leading to activation of NF-kappaB.
Lentsch
Alex B
AB
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0558, USA.
Pathrose
Peterson
P
Kader
Sarah
S
Kuboki
Satoshi
S
Collins
Margaret H
MH
Waltz
Susan E
SE
D000208:Acute Disease; D000818:Animals; D018893:Bronchoalveolar Lavage; D016207:Cytokines / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D055370:Lung Injury; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009573:Nitrites; D009195:Peroxidase / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D009195:Peroxidase; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051550:I-kappa B Kinase