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Early Radiation‐Induced Secretion of Gastrin‐Releasing Peptide (GRP) Mediates Late Pulmonary Fibrosis

Pulmonary fibrosis (PF), a devastating disease affecting >105 Americans, can have environmental, autoimmune, or idiopathic causes. In lung, pulmonary neuroendocrine cells secrete GRP in response to oxidant exposures. Previously, we showed early GRP elevation precedes PF in hyperoxic baboons. Also, GRP blockade given to mice twice weekly abrogates radiation (RT)‐induced pulmonary fibrosis at 20 wks. We have now tested the hypothesis that early GRP secretion mediates PF by using a C57L/J mouse model of RT‐induced PF, with prolonged, irreversible kinetics like human PF. 1‐24h post‐RT mice were injected IP with PBS, 2A11 (GRP‐blocking mAb), or 77427 (GRP‐blocking small molecule). Sham controls were not irradiated. Urine was collected every 6h for 24h pre‐ and post‐RT. Lung tissue sections 10‐15 weeks post‐RT were stained for collagen (Masson's trichrome), elastin (Hall's method), and α‐smooth muscle actin immunostaining (SMA, myofibroblast marker). Quantitative image analysis was performed on alveolar photomicrographs by blinded observers. Mice had tenfold‐elevated urine GRP levels 0‐6h post‐RT, which declined to 2‐fold elevated at 18‐24h, abrogated by GRP blockade 1h post‐RT. Multiplex analysis of lungs at 24h showed only IL‐10 elevation, prevented by GRP blockade 1h post‐RT. One dose of GRP blockade 24h post‐RT abolished parameters of PF 15‐wks later: increased interstitial collagen, elastin, and myofibroblasts. In conclusion, urine GRP is elevated before 24h post‐RT, prevented by GRP blockade, which also blocks pathological hallmarks of PF months later. GRP is a novel biomarker for PF and GRP blockade might prevent PF and its sequelae.