Table 1.

Lymphangiogenesis in fibrotic diseases.

Organs	Research Methods	Findings	References
Heart	Autopsied hearts after MI	・ Lymphangiogenesis was observed in healing stages with fibrosis.	[71]
	Rat models of MI	・ Administration of VEGF-C accereated lymphangiogenesis, leading to reducing cardiac inflammation, fibrosis, and dysfunction.	[72]
Lung	Human lung tissues and BALF	・ Areas of lymphatic vessels were correlated with the severeity of IPF. ・ Short-fragments of hyaluronic acid in BALF might mediate lymphatic endothelial cell growth. ・ CD11b+ alveolar macrophages in IPF could differenciate into lymphatic endothelial cells.	[74]
Kidney	Human kidney biopsies	・ The number of lymphatic vessels was correlated with the degree of tubulointerstitial fibrosis.	[49]
	Rat models of UUO	・ TGF-β1 promoted VEGF-C production in proximal tubular cells, collecting duct cells, and macrophages, leading to fibrosis-associated renal lymphangiogenesis.	[8]
	Cultured renal tubular cells, macrophages
	Mouse models of UUO	・ TGF-β1 and TNF-α induced VEGF-C production in proximal tubular cells and macrophages. ・ VEGF-D prevented direct inhibitory effects on lymphatic endothelial cell growth by TGF-β1.	[9]
	Cultured renal tubular cells, macrophages, lymphatic endothelial cells
	Rat models of proteinuric nephropathy	・ Suppression of lymphangiogenesis by anti-VEGFR3 antibody did not affect inflammation, fibrosis, and proteinuria.	[54]
	Mouse models of UUO, IRI	・ CTGF induced VEGF-C production in proximal tubular cells, leading to fibrosis-associated renal lymphangiogenesis. ・ CTGF bound to VEGF-C and inhibited VEGF-C-induced lymphatic endothelial cell growth.	[16]
	Cultured renal tubular cells, lymphatic endothelial cells
	Mouse models of UUO	・ Administration of VEGF-C accereated lymphangiogenesis, leading to reducing inflammation, TGF-β1 expression, and fibrosis.	[55]
Peritoneum	Human peritoneal biopsies	・ Expression of lymphatic vessels was correlated with the degree of peritoneal fibrosis. ・ TGF-β1 promoted VEGF-C production in mesothelial cells, leading to fibrosis-associated peritoneal lymphangiogenesis.	[10]
	Rat PF models induced by CG
	Cultured mesothelial cells
	Mouse PF models induced by MGO	・ Suppression of lymphangiogenesis by soluble VEGFR-3 improved deteriorated net ultrafiltration.	[69]

MI: myocardial infarction; VEGF: vascular endothelial growth factor; BALF: bronchoalveolar lavage fluid; IPF: idiopathic pulmonary fibrosis; UUO: unilateral ureteral obstruction; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; VEGFR-3: VEGF receptor-3; IRI: ischemia reperfusion injury; PF: peritoneal fibrosis; CG: chlorhexidine gluconate; MGO: methylglyoxal.