Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses

Oshima, Kaori
Han, Xiaorui
Ouyang, Yilan
Masri, Rana El
Yang, Yimu
Haeger, Sarah M.
McMurtry, Sarah A.
Lane, Trevor C.
Davizon-Castillo, Pavel
Zhang, Fuming
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses, K. Oshima, X. Han, Y. Ouyang, R. el Masri, Y. Yang, S. Haeger, S. McMurtry, T. Lane, P. Davizon-Castillo, F. Zhang, X. Yue, R. Vivès, R. J. Linhardt, E. Schmidt, American Journal of Physiology-Lung Cellular and Molecular Physiology 317, L667–L677, 2019.
Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to postseptic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, with an unclear role for endothelial cells. The pulmonary circulation is lined by an endothelial glycocalyx, a heparan sulfate-rich layer essential to pulmonary homeostasis. Heparan sulfate degradation occurs early in sepsis, leading to lung injury. Endothelial synthesis of new heparan sulfates subsequently allows for glycocalyx reconstitution and endothelial recovery. We hypothesized that remodeling of the reconstituted endothelial glycocalyx, mediated by alterations in the endothelial machinery responsible for heparan sulfate synthesis, contributes to CARS. Seventy-two hours after experimental sepsis, coincident with glycocalyx reconstitution, mice demonstrated impaired neutrophil and protein influx in response to intratracheal lipopolysaccharide (LPS). The postseptic reconstituted glycocalyx was structurally remodeled, with enrichment of heparan sulfate disaccharides sulfated at the 6-O position of glucosamine. Increased 6-O-sulfation coincided with loss of endothelial sulfatase-1 (Sulf-1), an enzyme that specifically removes 6-O-sulfates from heparan sulfate. Intravenous administration of Sulf-1 to postseptic mice restored the pulmonary response to LPS, suggesting that loss of Sulf-1 was necessary for postseptic suppression of pulmonary inflammation. Endothelial-specific knockout mice demonstrated that loss of Sulf-1 was not sufficient to induce immunosuppression in non-septic mice. Knockdown of Sulf-1 in human pulmonary microvascular endothelial cells resulted in downregulation of the adhesion molecule ICAM-1. Taken together, our study indicates that loss of endothelial Sulf-1 is necessary for postseptic suppression of pulmonary inflammation, representing a novel endothelial contributor to CARS.
American Journal of Physiology-Lung Cellular and Molecular Physiology 317, L667–L677
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
American Journal of Physiology - Lung Cellular and Molecular Physiology