Background: Lung transplantation remains hampered by a scarcity of viable donor lungs, partially attributed to donor lung injuries. Methods: Three porcine lung injury models were studied: infection-induced using lipopolysaccharide (LPS) (n=7), aspiration-induced using endotracheal gastric content (n=7), and injury using lavage and harmful ventilation (VILI) (n=7). Molecular and functional changes from before and after the establishment of lung injury were examined with histopathology, immunohistochemistry, cytokine levels, hemodynamics, and mass spectrometric analysis of lung tissue. The respiratory tract lining fluid was analyzed using exhaled breath particles. Results: T-cell proliferation and suppression of complement activation were unique to the gastric injury, while the VILI group displayed a unique activation of monocyte chemotaxis. The LPS injury exhibited an activation of stress response proteins. Alterations in the extracellular matrix, particularly the degradation of collagen type IV and increased elastin expression were identified as a consistent indicator of acute lung injury. Additionally, increases in exhaled particles and differential expression of proteins in the RTLF correlated with deteriorating lung function. Conclusions: Molecular analysis of the lung indicated distinct key differences and similarities of donor lung injury phenotypes. Analysis of various donor lung injuries suggests a heightened emphasis on the ECM for the restoration and rejuvenation of damaged donor lungs.