Table 2.

Featured biological markers, their functions and usage in monitoring of radiotherapy.

Biological Marker	Function in Radiation-Induced Lung Injury (RILI)	Research Studies	Conclusions	Reference
TGFβ1	TGFβ stimulates the differentiation of fibroblasts into myofibroblasts and promotes goblet cell hyperplasia, subepithelial fibrosis, epithelial damage, and airway smooth muscle hypertrophy	Higher TGF-β 2w/pre ratio (the ratio between TGFβ plasma level before and two weeks after RT) is associated with higher risk of RILI; the persistent high level of TGFβ after therapy suggests the occurrence of symptoms of radiation-induced inflammation	TGFβ plasma levels may identify individuals at high risk for the development of RILI	[39,43,44,45,46,47]
Il-6	Il-6 holds effects on the regulation of cellular functions such as growth, proliferation, differentiation, metabolism, the acute-phase reaction, angiogenesis, hematopoiesis, and apoptosis	Higher concentrations of Il-6, before and after treatment, are connected with the development of inflammation; overproduction of Il-6 in the acute radiation-induced process is associated with the risk and occurrence of severe RP	Il-6 can be used as a predictive marker of the RP development	[15,43,44,46,48]
Il-8	Il-8 is a neutrophil-, basophil-, and T-lymphocyte-activator and chemoattractant; Il-8 induces collagen synthesis and cell proliferation and has an anti-inflammatory effect	Lower baseline level of Il-8 is associated with higher risk of RILI (patients without inflammatory symptoms have about 4 times higher levels of Il-8 than the group of patients with the presence of symptoms)	The evaluation of Il-8 before therapy can be a good predictor for the risk of complications	[13,45,46,48,49]
Il-10	Il-10 downregulates inflammation by inhibiting the production of pro-inflammatory cytokines and reducing the activity of antigen-presenting cells	Levels of Il-10 are remained low in patients with RP throughout the treatment; a consistent increase of circulating Il-10 is observed at 2 weeks of treatment in patients without RP	The evaluation of Il-10 throughout the treatment may be a good predictor of RP	[50]
TNFα	TNFα stimulates the fibroblasts growth, secretion of ECM proteins, production of collagenases, and activation of cascades of other pro-inflammatory cytokines (IL-1, IL-6, IFN)	The early release of TNFα is a critical factor after lung irradiation; blocking of TNFα signaling via knockdown or using antisense oligonucleotides against the TNFα receptor can protect mouse lung from radiation injury; treatment with a recombinant TNFα receptor results in the regression of fibrinolytic lesions within damaged lungs	TNFα may indicate RP in its initial phase; correlation between the occurrence of RILI and the level of TNFα	[43,53,54,55,56]
SP-A and SP-D	Degradation of type II pneumocytes results in facilitated passage of SP-A and SP-D to the systemic circulation and increased levels of circulating SPs; SPs stimulate macrophages to production of pro-inflammatory cytokines (TGFβ, interleukins) and ROS	Serum and plasma levels of SP-D are elevated in patients with RP	Serum SP-D monitoring is a practical and useful method for the early detection of RP	[46,59,60,61,62]
KL-6	KL-6 demonstrates proliferative and anti-apoptotic effects and contributes in pulmonary fibrotic processes	An increased level of KL-6 at least 1.5 values of the upper limit of the reference range before radiotherapy correlates with a high risk of complications; serum KL-6 level correlates with severity and response to therapy in pulmonary fibrosis	Monitoring of the severity of RP; useful biomarker of pulmonary fibrosis activity	[46,59,66,68,69,70]

TGFβ—transforming growth factor β; Il—interleukin; TNFα—tumor necrosis factor α; SP—surfactant protein; KL-6—Krebs von den Lugen-6; RILI—radiation-induced lung injury; ECM—extracellular matrix; IFN—interferon; ROS—reactive oxygen species; RT—radiotherapy; RP—radiation-induced pneumonitis.