Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction

Abstract

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first‐year post‐transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose–response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study

“…These findings call into question the characterization of ALI or OP as “non‐immune” patterns of injury in lung allograft recipients 12 . Supporting this idea, recent data indicate plasma and lung fluid levels of select chemokines, including CXCL9 and CXCL10, are elevated at the time of ALI in particular and that the prognostic implications of ALI on CLAD risk are dependent on the presence of chemokine activation 21 . Together these observations underscore that novel immunosuppression strategies that disrupt cellular or humoral immune activation are needed to mitigate the influence of these graft injury histologies on long‐term lung recipient outcomes.…”

Ginsenoside Rh4 alleviates idiopathic pulmonary fibrosis by enhancing the CXCL9–CXCR3 axis

“…Previous research has indicated that mTORC2 orchestrates an upregulation of CXCR3 to curb hepatic fibrosis and enhances CXCR3/CXCL9 expression to alleviate dermal fibrosis (Richmond et al., 2023). Furthermore, there exists evidence underscoring the immunomodulatory effects of CXCR3/CXCL9 in fostering inflammation resolution and repair (Shino et al., 2022). Notably, the upregulation of CXCR3/CXCL9 has demonstrated an ability to impede activated collagen production in fibroblasts, thereby inhibiting the formation of fibrosis (Li et al., 2021).…”

Acute Rejection of the Lung Allograft: Phenotypes and Management

“…Biomarkers are emerging tools which may help identify which minimal rejection episodes may confer the greatest risk and warrant treating. One intriguing option is the chemoattractant CXCL9 which been shown to be elevated in BALF and serum in the setting of several underlying allograft injuries and predictive of future CLAD, though testing is not yet available in routine clinical practice and further study is needed [105,109,110].…”