Local complement activation is associated with primary graft dysfunction after lung transplantation
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Local complement activation is associated with primary graft dysfunction after lung transplantation. / Kulkarni, Hrishikesh S; Ramphal, Kristy; Ma, Lina; Brown, Melanie; Oyster, Michelle; Speckhart, Kaitlyn N; Takahashi, Tsuyoshi; Byers, Derek E; Porteous, Mary K; Kalman, Laurel; Hachem, Ramsey R; Rushefski, Melanie; McPhatter, Ja'Nia; Cano, Marlene; Kreisel, Daniel; Scavuzzo, Masina; Mittler, Brigitte; Cantu, Edward; Pilely, Katrine; Garred, Peter; Christie, Jason D; Atkinson, John P; Gelman, Andrew E; Diamond, Joshua M.
In: JCI insight, Vol. 5, No. 17, e138358, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Local complement activation is associated with primary graft dysfunction after lung transplantation
AU - Kulkarni, Hrishikesh S
AU - Ramphal, Kristy
AU - Ma, Lina
AU - Brown, Melanie
AU - Oyster, Michelle
AU - Speckhart, Kaitlyn N
AU - Takahashi, Tsuyoshi
AU - Byers, Derek E
AU - Porteous, Mary K
AU - Kalman, Laurel
AU - Hachem, Ramsey R
AU - Rushefski, Melanie
AU - McPhatter, Ja'Nia
AU - Cano, Marlene
AU - Kreisel, Daniel
AU - Scavuzzo, Masina
AU - Mittler, Brigitte
AU - Cantu, Edward
AU - Pilely, Katrine
AU - Garred, Peter
AU - Christie, Jason D
AU - Atkinson, John P
AU - Gelman, Andrew E
AU - Diamond, Joshua M
PY - 2020
Y1 - 2020
N2 - BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.
AB - BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.
U2 - 10.1172/jci.insight.138358
DO - 10.1172/jci.insight.138358
M3 - Journal article
C2 - 32750037
VL - 5
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 17
M1 - e138358
ER -
ID: 261235066