Local complement activation is associated with primary graft dysfunction after lung transplantation

Abstract

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. RESULTS. In 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. CONCLUSION. Complement 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.

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

“…Fourth, for certain outcomes, our sample size was such that there were differences in the levels of the markers between the two groups, but they did not always meet statistical significance (e.g., mortality signal in sC5b-9); one explanation is that our study was not specifically powered for that outcome, and additionally, there may be other factors outside of acute respiratory failure that contributed to a signal such as mortality. Additionally, as we and others have previously reported, smaller differences in circulating proteins, especially in the context of complement activation, become apparent when studied locally (Daamen et al ., 2020; Kulkarni et al ., 2020). Reports on local complement deposition in autopsy specimens from patients with COVID-19 support this hypothesis (Bradley et al ., 2020; Fox et al ., 2020; Macor et al ., 2021).…”

“…Participants were screened in duplicate for complement activation in the plasma using the soluble C5b-9 (sC5b-9) assay (BD OptEIA Human C5b-9 ELISA set, Franklin Lakes, NJ, USA) (Kulkarni et al ., 2020). Per the manufacturer, purified native human C3, C4, C5, C6, C7, C8 and C9 were tested in the BD OptEIA™ assay at ≥ 5 mg/ml and no cross-reactivity (value ≥ 470 pg/ml) was identified.…”

Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review

“… 114 , 115 Furthermore, in a randomized, double-blinded, multicenter trial, prereperfusion treatment with TP10, an inhibitor of C3 and C5 convertases, decreased the duration of mechanical ventilation after lung transplantation compared with the placebo group. 114 , 116 A more recent multicenter trial found that patients with PGD had increased bronchial alveolar lavage levels of complement activation fragments at 24 h posttransplantation. 114 These findings present complement targeted strategies as a potential treatment strategy for LIRI.…”

“… 114 , 116 A more recent multicenter trial found that patients with PGD had increased bronchial alveolar lavage levels of complement activation fragments at 24 h posttransplantation. 114 These findings present complement targeted strategies as a potential treatment strategy for LIRI.…”

Primary Graft Dysfunction

“…72 Finally, Kulkarni et al described higher BAL concentrations of complement activation fragments, including C1q, C2, C4, and C4b, among subjects with PGD compared with subjects without PGD, suggesting complement-targeted therapeutics may play role in mitigating severity of PGD. 121…”