Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity.
BACKGROUND
Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain.


OBJECTIVE
To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells.


METHODS
HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion.


RESULTS
HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation.


CONCLUSIONS
These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.
1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and.
Jamie L
JL
Todd
Xingan
X
Wang
Seichiro
S
Sugimoto
Vanessa E
VE
Kennedy
Helen L
HL
Zhang
Elizabeth N
EN
Pavlisko
Fran L
FL
Kelly
Howard
H
Huang
Daniel
D
Kreisel
Scott M
SM
Palmer
Andrew E
AE
Gelman
D000328:Adult; D064591:Allografts / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism; D011183:Postoperative Complications / Q000276:immunology* / Q000378:metabolism; D013577:Syndrome
D015415:Biomarkers; D006820:Hyaluronic Acid