Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity

Jamie L. Todd, Xingan Wang, Seiichiro Sugimoto, Vanessa E. Kennedy, Helen L. Zhang, Elizabeth N. Pavlisko, Fran L. Kelly, Howard Huang, Daniel Kreisel, Scott M. Palmer, Andrew E. Gelman

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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 ofHAsynthases. Murine orthotopic lung recipients with established tolerance were treated with low- or highmolecular- weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. Measurements and Main 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 plasmaHA 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, TLRdependent 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.

Original languageEnglish
Pages (from-to)556-566
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number5
DOIs
Publication statusPublished - Mar 1 2014
Externally publishedYes

Fingerprint

Bronchiolitis Obliterans
Hyaluronic Acid
Innate Immunity
Allografts
Lung
Molecular Weight
Toll-Like Receptor 2
Protein Deficiency
Toll-Like Receptor 4
Isoantigens
Lung Transplantation
Therapeutic Irrigation
Bronchoalveolar Lavage
Neutrophils
Fibrosis
Ligands

Keywords

  • Bronchiolitis obliterans syndrome
  • Hyaluronan
  • Innate immunity
  • Lung transplantation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. / Todd, Jamie L.; Wang, Xingan; Sugimoto, Seiichiro; Kennedy, Vanessa E.; Zhang, Helen L.; Pavlisko, Elizabeth N.; Kelly, Fran L.; Huang, Howard; Kreisel, Daniel; Palmer, Scott M.; Gelman, Andrew E.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 189, No. 5, 01.03.2014, p. 556-566.

Research output: Contribution to journalArticle

Todd, Jamie L. ; Wang, Xingan ; Sugimoto, Seiichiro ; Kennedy, Vanessa E. ; Zhang, Helen L. ; Pavlisko, Elizabeth N. ; Kelly, Fran L. ; Huang, Howard ; Kreisel, Daniel ; Palmer, Scott M. ; Gelman, Andrew E. / Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 189, No. 5. pp. 556-566.
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abstract = "Rationale: 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. Objectives: 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 ofHAsynthases. Murine orthotopic lung recipients with established tolerance were treated with low- or highmolecular- weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. Measurements and Main 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 plasmaHA 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, TLRdependent 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.",
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T1 - Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity

AU - Todd, Jamie L.

AU - Wang, Xingan

AU - Sugimoto, Seiichiro

AU - Kennedy, Vanessa E.

AU - Zhang, Helen L.

AU - Pavlisko, Elizabeth N.

AU - Kelly, Fran L.

AU - Huang, Howard

AU - Kreisel, Daniel

AU - Palmer, Scott M.

AU - Gelman, Andrew E.

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Y1 - 2014/3/1

N2 - Rationale: 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. Objectives: 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 ofHAsynthases. Murine orthotopic lung recipients with established tolerance were treated with low- or highmolecular- weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. Measurements and Main 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 plasmaHA 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, TLRdependent 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.

AB - Rationale: 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. Objectives: 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 ofHAsynthases. Murine orthotopic lung recipients with established tolerance were treated with low- or highmolecular- weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. Measurements and Main 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 plasmaHA 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, TLRdependent 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.

KW - Bronchiolitis obliterans syndrome

KW - Hyaluronan

KW - Innate immunity

KW - Lung transplantation

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