Figure 1. Hypothesis—The vagus nerve promotes fibrotic progression through several pathways.

Myofibroblasts at fibrotic lesions are cells responsible for synthesis and deposition of collagen that leads to fibrosis. TGF-β transforms fibroblasts to myofibroblasts. IL-4 serves as an inducer of TGF-β. Activation of the vagal efferent nerve releases acetylcholine, which stimulates fibroblasts by acting on acetylcholine receptors (or by increasing the level of TGF-β) to synthesize collagen. Activation of vagal afferents may produce the axon reflex to release neuropeptides, which polarize macrophages toward a fibrogenic M2 phenotype. Both TGF-β and IL-4 also promote the M2 phenotype. Arrows indicate interaction direction between fibrogenic factors. The dash line squared variables were tested in the protocol to evaluate the effect of vagotomy on bleomycin-induced lung fibrosis. M2, Type 2 (alternatively activated) macrophages; TGF-β, transforming growth factor-β; IL-4, Interleukin-4; α-SMA, α-smooth muscle actin.