Network analysis of lung tissue repair processes in response to influenza-induced damage identifies tissue remodeling factor TIMP-1 in recovery (P3180)

Abstract

Abstract Mild and severe influenza infections clearly differ in disease resolution, likely due to variations in the host’s repair response to lung tissue damage. Over 60 protein factors involved in lung tissue repair at multiple stages of a mild and a severe influenza infection (early, mid-stage, viral clearance, and after viral clearance) were quantified and organized into an interaction network. Factors characteristic of all phases of tissue repair—coagulation, inflammation, migration and proliferation, and remodeling—were up-regulated in mouse whole lung tissue after both types of infections. Differences in intensity and timing of these factors, particularly in the later three stages of wound repair, were observed. Network analysis allowed for identification of a key node in the repair pathway important in tissue remodeling, TIMP-1. TIMP-1-/- mice were more susceptible to PR/8 infection independently of viral titer or inflammatory immune responses. However, respiratory analyses showed exacerbated responses to both infections, suggestive of dysregulated lung function during attempted resolution of disease. We demonstrate the utility of systems biology for understanding complex, multi-layered, integrated biological processes such as wound healing, and in identification of previously overlooked factors involved in such processes. We also demonstrate the contribution of TIMP-1, a protein not involved in viral control, coagulation, or inflammation, in recovery from influenza infection.