Humidifier disinfectant-associated lung injury (HDLI) is affected by long-term inhalational exposure to toxic polyhexamethylene guanidine (PHMG)-containing humidifier disinfectant (HD) and characterized by the rapid progression of respiratory failure with lung fibrosis and frequent air leak syndrome with high mortality. However, the underlying mechanism of the disease is not yet understood. This is the first multi-omics (transcriptomics and proteomics) and network study using human lung tissue and identified a potential MMP2-mediated different mechanism between child and adult in HDLI: adult-specific accelerated TGFβ/SMAD signaling pathway under the pre-exposure to environmental toxic materials, whereas child-specific integrin-mediated signaling pathway.