Table 1.

Summary of soluble mediators implicated in epithelial repair and fibrosis.

Mediator	Effects on Repair	Implication in Fibrosis	Key References
Growth factors
EGF	EGF and its receptor upregulated after airway injury. Promotes migration and wound healing of primary airway epithelial cells in vitro. EGF receptor dominant negative mutant impair basal cell proliferation after injury in vivo.	Overexpression of EGF receptor in bronchial epithelium and type 2 pneumocytes of IPF patients. EGFR inhibition by gefitinib results in development of pulmonary fibrosis.	[62,64,66,132,133]
IGF	Increases expression of anti-apoptotic proteins in airway epithelial cells. Also associated with increased ECM deposition and fibrosis.	Increased IGF-1 present in IPF tissue and associated with decreased pulmonary function and disease progression. Inhibition of IGF-1R by OSI-906 delayed progression and decreased mortality in murine lung.	[73,74,134]
VEGF	Alveolar cell proliferation and enhanced wound healing in vitro	VEGF-A from AT2 cells may play protective role and aid regeneration of wall defects. VEGF-Axxxa family is profibrotic and VEGF-Axxxb is inhibitory.	[79,80,135,136]
TGFα	Increased wound healing of alveolar cells in vitro.	Chronic conditional expression of TGFα induces pulmonary fibrosis independently of inflammation in adult murine lung.	[85,137]
Lipid mediators
PGE2	Enhanced proliferation and wound closure of airway epithelium in vitro.	Inhibition of the PGE2 degrading enzyme, 15-Prostaglandin dehydrogenase, increases PGE2 concentrations and ameliorates lung function and increases proliferation in a bleomycin mouse model of pulmonary fibrosis. Potent downregulator of fibroblast activation.	[94,95,138,139]
Lipoxin A4	Promotes primary alveolar epithelium proliferation and wound closure, inhibits apoptosis and cytokine production in vitro.	Decreased lipoxin A4/LTB4 ratio advances fibrosis. Upregulation of ALX receptor associated with reduced collagen accumulation in vivo.	[100,101,139]
RvD3	Increased epithelial proliferation and reduced inflammation and organ injury after acid-induced lung injury in vivo.		[103]
Cytokines
CCR3 ligands	Upregulated epithelial proliferation and chemotaxis and enhanced wound repair in vitro.	Lung fibrotic response limited by neutralising CCR3 receptor, expression of profibrotic mediators decreased.	[110,140]
IL-22	Promotes airway epithelial proliferation and protects against lung dysfunction, morbidity, and fibrosis after influenza infection in vivo.	Protective role against severe fibrosis following bacterial infection.	[111,112]
Other
Airway mucin gene (MUC5B)	Attenuates ciliated cell differentiation in repair. MUC5B disrupts alveolar repair by interfering with the interaction between AT2 and the matrix.	Promoter polymorphism is a strong genetic risk for IPF.	[141,142]