A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease.
The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection.
Comparative Pathology Program, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, United States. Electronic address: mychang@u.washington.edu.
Mary Y
MY
Chang
Fukushima Medical University School of Medicine, Department of Pulmonary Medicine, Fukushima, Japan.
Yoshinori
Y
Tanino
Comparative Pathology Program, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, United States.
Veronika
V
Vidova
Hope Heart Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Michael G
MG
Kinsella
Hope Heart Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Christina K
CK
Chan
Hope Heart Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Pamela Y
PY
Johnson
Hope Heart Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Thomas N
TN
Wight
Comparative Pathology Program, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, United States; Division of Pulmonary/Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
Charles W
CW
Frevert
D000818:Animals; D004926:Escherichia coli / Q000472:pathogenicity; D005786:Gene Expression Regulation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000235:genetics; D053675:Versicans / Q000096:biosynthesis*
D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053675:Versicans; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases
Hyaluronan; Lung; Macrophage; TLR-4; Versican