Distinct Expression Patterns of Alveolar “Alarmins” in Subtypes of Chronic Lung Allograft Dysfunction

Abstract

The long-term success of lung transplantation is limited by chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the alveolar alarmin profiles in CLAD subtypes, restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). Bronchoalveolar lavage (BAL) samples were collected from 53 recipients who underwent double lung or heart-lung transplantation, including patients with RAS (n ¼ 10), BOS (n ¼ 18) and No CLAD (n ¼ 25). Protein levels of alarmins such as S100A8, S100A9, S100A8/A9, S100A12, S100P, high-mobility group box 1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in BAL fluid were measured. RAS and BOS showed higher expressions of S100A8, S100A8/A9 and S100A12 compared with No CLAD (p < 0.0001, p < 0.0001, p < 0.0001 in RAS vs. No CLAD, p ¼ 0.0006, p ¼ 0.0044, p ¼ 0.0086 in BOS vs. No CLAD, respectively). Moreover, RAS showed greater up-regulation of S100A9, S100A8/A9, S100A12, S100P and HMGB1 compared with BOS (p ¼ 0.0094, p ¼ 0.038, p ¼ 0.041, p ¼ 0.035 and p ¼ 0.010, respectively). sRAGE did not show significant difference among the three groups (p ¼ 0.174). Our results demonstrate distinct expression patterns of alveolar alarmins in RAS and BOS, suggesting that RAS and BOS may represent biologically different subtypes. Further refinements in biologic profiling will lead to a better understanding of CLAD.

Epithelial cell death markers in bronchoalveolar lavage correlate with chronic lung allograft dysfunction subtypes and survival in lung transplant recipients—a single‐center retrospective cohort study

“…Our results suggest that BAL epithelial cell death biomarkers, in particular, M65, could potentially improve the diagnostic accuracy of CLAD and help distinguish BOS from RAS in the absence of adequate lung volume measurements. Similar to our observations, other BAL proteins have been described recently as having a distinct expression pattern in RAS compared to BOS, with upregulation of innate immune and injury markers . Assessing multivariable biomarker signatures will be an important focus in future research.…”

The role of biomechanical anatomical modeling via computed tomography for identification of restrictive allograft syndrome

“…Furthermore, biological distinctions between RAS and BOS have been suggested; implying that therapeutic strategies for RAS and BOS could be different. Therefore, the precise differentiation of RAS from BOS has great clinical importance …”

“…Therefore, the precise differentiation of RAS from BOS has great clinical importance. 5,6 The current diagnosis of CLAD and its subtypes relies on pulmonary function test (PFT) results: CLAD is defined as irreversible decline in forced expiratory volume in 1 second (FEV 1 ) of <80% of the baseline value, 7 and RAS is originally defined as CLAD with irreversible decline in total lung capacity (TLC) <90% of the baseline. 8 However, the TLC measurement is not routinely performed in LTx recipients.…”

Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure

“…Compared with the much better known BOS clinical phenotype, patients with RAS experience a worse prognosis (3.5 versus 1.5 years); the reasons for this difference in prognosis are poorly understood [7]. Patients affected by RAS appear to progress in a more stepwise pattern [8], that might be driven by intermittent up-regulation of pro-inflammatory mediators [9,10] during episodes of diffuse alveolar damage [11,12] similar to those observed in patients with idiopathic pulmonary fibrosis (IPF).…”