Figure 2.

Diabetes-associated persistent DSB signaling, senescence and SASPs modulates the normal repair of idiopathic pulmonary fibrosis. Diabetes-associated perturbed cellular metabolism is cumulatively linked to diabetic pneumopathy. Elevation of ROS, disturbed NAD⁺/NADH equilibrium, and non-specific modifications of active biomolecules affect the integrity of the genome and the kinetics of DNA repair. The absence of timely DNA repair activates persistent DNA damage signaling, followed by an irreversible cell cycle arrest, cellular senescence and senescence-associated secretory phenotype (SASP). The SASP releases various pro-inflammatory cytokines such as IL-1α/β, IL-6, IL-8, TGF-β, ICAM, Mcp1 & TNF-α. These cytokines act autocrine and paracrine by altering the cellular homeostasis to maladaptive genetic transformations resulting in severe inflammation and organ fibrosis. The cytokines released from the SASP zone, such as IL-6, IL-8 and TGF-β, activate the fibrotic program via the JAK-STAT pathway. Therefore, the accumulated ECM compromises the functional integrity of diabetic lungs and transforms the parenchymal organ to idiopathic pulmonary fibrosis.