Cytokines and radiation-induced pulmonary injuries

Abstract

Radiation therapy is one of the most common treatment strategies for thorax malignancies. One of the considerable limitations of this therapy is its toxicity to normal tissue. The lung is the major dose-limiting organ for radiotherapy. That is because ionizing radiation produces reactive oxygen species that induce lesions, and not only is tumor tissue damaged, but overwhelming inflammatory lung damage can occur in the alveolar epithelium and capillary endothelium. This damage may result in radiation-induced pneumonitis and/or fibrosis. While describing the lung response to irradiation generally, the main focus of this review is on cytokines and their roles and functions within the individual stages. We discuss the relationship between radiation and cytokines and their direct and indirect effects on the formation and development of radiation injuries. Although this topic has been intensively studied and discussed for years, we still do not completely understand the roles of cytokines. Experimental data on cytokine involvement are fragmented across a large number of experimental studies; hence, the need for this review of the current knowledge. Cytokines are considered not only as molecular factors involved in the signaling network in pathological processes, but also for their diagnostic potential. A concentrated effort has been made to identify the significant immune system proteins showing positive correlation between serum levels and tissue damages. Elucidating the correlations between the extent and nature of radiation-induced pulmonary injuries and the levels of one or more key cytokines that initiate and control those damages may improve the efficacy of radiotherapy in cancer treatment and ultimately the well-being of patients.

Fig. 1.

Structural scheme of an alveolus in the lung under physiological conditions. The lung alveoli consist of an epithelial layer and an extracellular matrix surrounded by capillaries. The major cells in the alveolar wall comprise pneumocytes Types I and II, and alveolar macrophages. The gas-exchanging region, the alveolar–capillary barrier, is formed by Type I alveolar epithelial cells and the endothelial cells of the capillaries, and consists of the basement membrane between these cells. The interstitium of the alveoli is occupied by resident fibroblasts and forms an extracellular matrix.

Fig. 2.

(A) Latent phase of radiation-induced pulmonary injury: radiation-induced changes at molecular and cellular levels. The subunit most sensitive to ionizing radiation is the alveolar–capillary barrier (ACB). The cytoplasm of endothelial cells is hypertrophied and vacuolated, resulting in increased microvascular permeability. Ultrastructural interstitial edema can be found in the ACB complex. AECII has decreased the number of lamellar bodies and releases impaired surfactant inside the alveoli. AECI reacts by swelling and necrosis, which results in basement membrane denudation. (B)Acute phase of radiation-induced pulmonary injury (radiation pneumonitis). This phase is characterized mainly by an inflammatory process triggered by damage to lung parenchyma, epithelial cells, vascular endothelial cells, and stroma. It involves the induction of proinflammatory cytokines and chemokines that recruit immune cells in the lung tissue. Recruited peripheral neutrophils, monocytes differentiated into macrophages and the cytokines produced by different cell types are most responsible for the acute inflammation.