Here, through ex vivo models, bioinformatics and human lung fibrosis tissue studies, we extend these observations leading to the discovery that HIF pathway activation promotes pathologic pyridinlone collagen crosslinking and tissue stiffness by disproportionate induction of collagen-modifying enzymes relative to TGFβ-induced collagen fibril synthesis. This evidence concerns the gene TGFB1 and pulmonary fibrosis.