*Purpose: Pleuroparenchymal fibroelastosis (PPFE) is a rare but distinctive manifestation of interstitial lung disease (ILD) characterized by a highly elastotic pattern of lung fibrosis. Its etiology is not known. There is no consensus on a set of diagnostic criteria. As its radiographic findings overlap with those of other interstitial lung diseases, PPFE lies within the differential diagnosis for, and may coexist with, other fibrotic interstitial lung diseases. It might evolve from an underlying fibrotic process. The purpose of this study was to explore the underling pathogenesis of this condition by looking at an interesting group of patients with Usual Interstitial Pneumonia (UIP) that underwent a single lung transplant, and subsequently developed PPFE in the native lungs left in the recipients.

*Methods: The pathology database was searched using key words of lung transplant for UIP. The clinical records, and pathology reports were reviewed. Total RNA was extracted from paraffin embedded tissue of explanted native lungs before and after the single lung transplant. Multiplexed mRNA measurement was performed using nCounter and fibrosis panel (NanoString Technologies).

*Results: Four patients were identified who had unilaterally lung transplantation for fibrotic interstitial lung disease (UIP). In all these patients the 2^nd native lung tissue was subsequently analyzed because the patient developed a malignancy (2 patients) or received 2^nd lung transplant (1 patient) or passed away (1 patient). All these lungs, initially diagnosed as UIP, showed the phenotype of PPFE. All four patients were taking the same immunosuppressive regimen of tacrolimus, azathioprine, and prednisone. PPFE was diagnosed between 12 to 48 months after lung transplantation. Compared to the level of mRNA expression in explanted lungs with UIP at transplantation, the lungs with PPFE showed an upregulation of lymphotoxin beta (LTB), CD8A, AMOLT2 (Angiomotin like 2), RAC3 (Rac family small GTPase 3), and BCL2 by 3.83, 2.81, 2.1, 1.93, and 1.72 in log 2 folds, respectively, which are involved in the regulation of NF-kappa B, Hippo, Wnt, and Hedgehog signaling pathways (all p<0.001).

*Conclusions: Four patients transplanted for fibrotic interstitial lung disease on similar immunosuppressive regimens have presented months to years after single lung transplantation to show a different diagnosis of PPFE in the second native lung with a different genotype in the fibrotic RNA panel analyzed. The main intervention in all these patients was the addition of a triple immunosuppressive regimen. It is therefore likely that the different gene expression and phenotype between UIP pre-transplant and PPFE post-transplant in the native lungs is due to immunosuppressive therapy induced immunomodulation in key genes in the fibrotic pathways.

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