Abstract Background Crohn’s disease (CD) is a chronic inflammatory bowel disease characterized by transmural inflammation and progressive intestinal damage. Intestinal fibrosis leading to stricture formation remains a major cause of surgery in CD, yet effective anti-fibrotic therapy is lacking. Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) regulate mesenchymal proliferation and extracellular matrix (ECM) synthesis in other fibrotic organs, but their role in CD-associated intestinal fibrosis remains unclear. This study aimed to evaluate the PDGF/PDGFR signaling pathway across serum, tissue, and in vitro fibroblast models to elucidate its involvement in intestinal fibrosis in CD. Methods Serum levels of platelet activation marker CD40 ligand (CD40L) and PDGF isoforms (PDGF-AA, -AB, -BB) were measured by ELISA in CD, ulcerative colitis (UC), and healthy controls. (2) Immunohistochemistry for PDGFRα and PDGFRβ was conducted on intestinal samples from CD patients with fibrostenotic lesions, UC patients with active inflammation, and non-IBD controls. (3) Human intestinal myofibroblasts (CCD-18Co) were stimulated with recombinant PDGF-BB (20 ng/mL), alone or in combination with selected pro-inflammatory cytokines, and mRNA expression of collagen I (COL1A1) was analyzed by real-time PCR using GAPDH as an internal control. Results Serum CD40L, PDGF-AB, and PDGF-BB were significantly elevated in CD (0.96 ± 0.75 ng/mL) and UC (1.18 ± 0.75) compared with controls (0.38 ± 0.38)(all p 0.05). PDGF-AB levels were 1027 ± 598 pg/mL (CD), 1210 ± 575 (UC), and 670 ± 426 (controls), while PDGF-BB levels were comparable among patients with CD, UC, and controls. PDGF-AA increased in CD (779 ± 529 vs 419 ± 247, p 0.05) but not in UC (p = 0.06). (2) PDGFRα and PDGFRβ were markedly up-regulated in CD and UC tissues compared with controls. PDGFRβ was strongly expressed in fibroblast-like and perivascular cells in the submucosa and muscularis layers of fibrostenotic CD (Figure), while PDGFRα localized mainly in submucosal stroma near mucosal glands. Control tissues showed only faint subepithelial staining. (3) PDGF-BB enhanced COL1A1 mRNA expression in vitro, while cytokine co-stimulation showed variable, non-synergistic trends. Conclusion Our integrated analysis across serum, tissue, and fibroblast models demonstrates that PDGF, particularly PDGF-BB, and PDGFRβ are up-regulated in IBD and contribute to intestinal fibrosis by promoting fibroblast activation and ECM production. PDGF signaling appears partially independent of active inflammation, suggesting a chronic role in fibrotic remodeling. The PDGF/PDGFR pathway may represent a promising therapeutic target for preventing fibrostenotic complications in Crohn’s disease. Conflict of interest: Ito, Yuka: No conflict of interest Yagi, Naoto: No conflict of interest Sano, Yasuki: No conflict of interest Ms. Honzawa, Yusuke: No conflict of interest Saito, Eiko: No conflict of interest Naganuma, Makoto: No conflict of interest
Ito et al. (Thu,) studied this question.