Abstract

Rationale. PAP is a an ultra-rare disease where a perturbation in surfactant homeostasis results in its accumulation within airspaces, thus impairing gas transfer. WLL currently remains the therapeutic standard, even if it may induce complete resolution of the disorder only in 30% of patients. Aim. To characterize the gene network able to predict the outcome of the WLL, i.e. total resolution/persistent improvement vs transient resolution/progressive deterioration. Methods. We conducted a gene interaction network analysis, with web-based software (esyN), to calculate hub and bottleneck genes previously investigated by a microarray analysis (1), performed on the PBMCs of 16 PAP patients treated with WLL and followed for 24 months. Hub genes were identified by the number of interactions within the network. Bottleneck genes were identified by calculating the betweenness centrality index (BCI) for each gene in the network. BCI reflects the amount of control that a gene exerts over the interactions of other genes in the network. Results. We found that SMAD3, which acts as a mediator of the profibrotic signals initiated by TGF-ß and SYNCRIP, which plays a role in multiple aspects of mRNA maturation, are top ranked hubs genes. Interestingly, SMAD3 is also the top ranked bottleneck gene. Conclusion. The SMAD3 transcription factor seems to be the central mediator and conductor of the gene network involved in the response to the WLL treatment in PAP patients.

1- M Zorzetto, et al. A gene network to predict the clinical response to whole lung lavage (WLL), in pulmonary alveolar proteinosis (PAP). ERS Annual Congress, Milano, Italy, September 9-13, 2017.