CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction

Abstract

Rationale: After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process.

Objectives: Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology.

Methods: Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates.

Measurements and main results: There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD.

Conclusions: DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.

Figure 1.

Study profile. A1 = grade A1; A2 = grade A2; A3 = grade A3; A4 = grade A4; AR = acute rejection; DAD = diffuse alveolar damage; LB = lymphocytic bronchiolitis; OP = organizing pneumonia.

Figure 2.

Prevalence of pathologic findings by time from transplant. AR = acute rejection (grade A2 or higher); DAD = diffuse alveolar damage; LB = lymphocytic bronchiolitis, OP = organizing pneumonia.

Figure 3.

Kaplan-Meier plot for freedom from chronic lung allograft dysfunction in lung transplant recipients with and without ever having an episode of diffuse alveolar damage (DAD).

Figure 4.

Kaplan-Meier plot for allograft survival in lung transplant recipients with and without ever having an episode of diffuse alveolar damage (DAD). Allograft survival = freedom from death or retransplant.

Figure 5.

Immunohistochemistry demonstrating (A) CXCL9 and (B) CXCL10 expressed from allograft airway bronchial epithelial cells (green arrows), subepithelial (dark blue arrows) and interstitial (light blue arrows) infiltrating mononuclear cells, and alveolar macrophages (black arrows). (C) CXCL11 expressed from allograft pulmonary vascular endothelial cells (red arrows). (D) CXCR3 expressed from airway bronchial epithelial cells, infiltrating mononuclear cells, and alveolar macrophages.