The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury.
Acute lung injury (ALI), a severe respiratory syndrome, develops in response to numerous insults and responds poorly to therapeutic intervention. Recently, cDNA microarray analyses were performed that indicated several pathogenic responses during nickel-induced ALI, including marked macrophage activation. Macrophage activation is mediated, in part, via the receptor tyrosine kinase Ron. To address the role of Ron in ALI, the response of mice deficient in the cytoplasmic domain of Ron (Ron tk-/-) were assessed in response to nickel exposure. Ron tk-/- mice succumb to nickel-induced ALI earlier, express larger, early increases in interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-2, display greater serum nitrite levels, and exhibit earlier onset of pulmonary pathology and augmented pulmonary tyrosine nitrosylation. Increases in cytokine expression and cellular nitration can lead to tissue damage and are consistent with the differences between genotypes in the early onset of pathology and mortality in Ron tk-/- mice. These analyses indicate a role for the tyrosine kinase receptor Ron in ALI.
McDowell
Susan A
SA
Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
Mallakin
Ali
A
Bachurski
Cindy J
CJ
Toney-Earley
Kenya
K
Prows
Daniel R
DR
Bruno
Theresa
T
Kaestner
Klaus H
KH
Witte
David P
DP
Melin-Aldana
Hector
H
Degen
Sandra J F
SJ
Leikauf
George D
GD
Waltz
Susan E
SE
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054412:Chemokine CCL8; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis; D009532:Nickel / Q000633:toxicity*; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced*; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; C515453:CCL8 protein, human; C515454:Ccl8 protein, mouse; D018932:Chemokine CCL2; D054412:Chemokine CCL8; D016207:Cytokines; D018076:DNA, Complementary; D015850:Interleukin-6; D018945:Monocyte Chemoattractant Proteins; D009573:Nitrites; D011956:Receptors, Cell Surface; D014443:Tyrosine; D009532:Nickel; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D000077191:Wortmannin