Local and Systemic Pathogenesis and Consequences of Regimen-Induced Inflammatory Responses in Patients with Head and Neck Cancer Receiving Chemoradiation
Table 1
Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses.
Mucosal injury
Relevant clinical consequences
(1) Initiation: oxidative stress and the innate immune response
Cellular damage induced by CT-RT (i) X-rays or mucotoxic drugs cause direct DNA break [28, 37]. (ii) Generation of ROS [38]. (iii) ROS damage lipids, DNA, connective tissue, and other biomolecules [39–41]. (iv) Cells die in epithelia, endothelia [62, 63], and submucosal tissue [28].
Release of inflammatory substances The components passively released from injured cells become a danger signal that alert the host of the dying cells and play an integral role in initiating toxicity [15]: (i) intracellular proinflammatory CRAMP (e.g., HMBG1 [64, 65], mitochondrial derived substances [40] ect.), (ii) intracellular enzymes (lysosomial), which activate extracellular proinflammatory DAMPs [66, 67] (which in turn activate other cascades, i.e., clotting, fibrinolytic, and kin cascades), (iii) altered redox state of the injured tissue [44], (iv) presynthesised interleukins (IL-1, IL-33) [68–70], (v) released intracellular hidden antigens which activate Complement via antibodies (Complement can be regarded both as a PRR system and an effector system [71, 72]).
Silent phase
(2) Upregulation/activation
(i) Activation of PRR, IL-1R, and RAGE receptors of the host’s innate immune system [15, 53] and of the peripheral nociceptive nervous fibres [73, 74]. (ii) The main canonical pathways associated with the development of CT-RT mucositis [11] as follows: (1) nitrogen metabolism (2) TLR signalling (3) NF-κB signalling (4) B cell receptor signalling (5) PI3K/AKT signalling (6) G2/M DNA damage checkpoint (7) SAPK/JNK signalling (8) P38 MAPK signalling (9) Wnt/B-catenin signalling (10) glutamate receptor signalling (11) integrin signalling (12) VEGF signalling (13) IL-6 signalling (14) death receptor signalling
Inflammation: transient faint erythema and pruritus that can develop during the first hours after irradiation [75, 76].
(3) Signal amplification and feedback
Local effects: intracellular and intercellular signalling loops
Local inflammation: Oedema, Cellular (mononuclear cells/macrophage and neutrophil) infiltration Epithelial thinning: hypersensitiveness Vasodilatation: erythema
Abscopal effects and toxicities: systemic and interorgan signalling [71]) (Figure 1)
(i) Elevated serum levels of NF-B, TNF-, IL-1 and IL-6 [86, 87] (ii) Genetic changes in peripheral blood monocytes [11]. (iii) Plasma cascades (Complement, coagulation, fibrinolytic, and kallikrein-kinin systems) [71] (iv) Acute phase proteins (Pentraxins—C-RP/SAP, Factor XII, Complement proteins ect.) [71] (v) HPA axis activated by circulating cytokines (IL-6) and by peripheral nervous system [88, 89]
Altered body temperature and altered metabolisms Fatigue [90] Cachexia [91–93]. SIRS [94]
(4) Ulcerative/microbiological phase
(i) Mucosal barrier injury (ii) Bacterial colonisation: increases follow, not precede, ulceration/MBI [95, 96] (iii) Microflora shifts due to CT, xerostomia, antibiotic use, and neutropenia. (iv) Microorganisms penetrate the disrupted mucosa and stimulate infiltrating macrophages to produce additional proinflammatory cytokines.
Ulceration Colonisation Local infection.
Cachexia: weight loss > 5% or BMI < 20 plus decreased muscle strength, fatigue, anorexia, low lean mass index, and abnormal biochemistry (increased C-RP and IL-6 inflammatory markers, anaemia, and low serum albumin) [97, 98]. Abbreviations see the text.
