Target cells in radiation pneumopathy

Abstract

Radiation pneumopathy is the reaction of the organ lung to radiation effects in various target cells. It starts as an exudative inflammation, with the clinical picture of interstitial pneumonia 6–12 weeks after irradiation, and proceeds to a productive chronic inflammation lasting several months and terminating, as other chronic inflammations do, in scar formation, called lung fibrosis. Lung fibrosis is the common end point after lung damage from a wide range of damaging agents. The pathogenetic process leading to the signs and symptoms of radiation pneumopathy is an integrated response of the complex organization of lung tissue. Clinical and pathologic data in patients do not support the hypothesis that the early inflammatory phase of radiation “pneumonitis” and late “radiation fibrosis” are independent pathogenetic processes in the same way as acute radiodermatitis and subcutaneous fibrosis are separate pathologic entities. The target cell population that initiates the pathogenetic process in the lung is not known, and it has been suggested that no single identifiable target exists. The entire process is the result of complex functional alterations in endothelial cells, pneumocytes, macrophages, and other resident and transient cells. No evidence has been found for a role of stem cell sterilization, for impaired transit cell proliferation, or for hypoplasia, which is the hallmark of other acute inflammatory normal tissue damage (i.e., in the mucosa). The radiobiologic concepts developed in cellular radiobiology are not adequate for the quantitative analysis of radiation pneumopathy. A new analytical framework based on structurally defined intercellular interaction by signaling molecules and their activation needs to be developed. This would not be only an abstract radiobiologic paradigm but would be the key to the development of potential therapeutic interventions in irradiated patients.

Introduction

Lung cancer presents a major challenge to radiation oncology. This is not because of extraordinary radioresistance of the different histologic types of lung cancer but rather due to their tendency to infiltrate early into large parts of the organ of origin (i.e., the lung), which, unfortunately, is the most radiosensitive vitally important organ in the body. Recent studies with deoxyglucose positron emission tomography have demonstrated that, in particular in locally advanced non–small-cell lung cancer, much more often than previously assumed, clinically manifest tumor is present in the contralateral lymph nodes and at some distance from the primary tumor and the bulk of affected mediastinal lymph nodes (1). To include all of this clinical tumor volume in a single primary target volume would often lead to unacceptable volumes. Therefore, the clinical problem of critical targets for lung cancer is not so much the radiobiology of lung cancer. The main problem that limits the success rate of radiotherapy (RT) in lung cancer is the radiosensitivity of the normal tissue into which the tumor infiltrates and which, therefore, has to be given very high radiation doses. With present RT techniques and radiobiologic knowledge about the possibilities of modification of radiation effects, they often exceed local normal tissue tolerance.

Radiation-induced lung damage, radiation pneumopathy, is a continuous process. Subclinical early damage in pneumocytes type I progresses to an acute interstitial inflammation at 6–12 weeks after the onset of RT and further to lung fibrosis after many months and years. In patients, the different phases of this pathologic process can best be diagnosed using radiologic methods such as plain chest X-rays or particularly well using CT.

The radiologic picture of radiation pneumonitis is characterized by inhomogeneous opacity of the irradiated volume and increased density of septal structures. The clinical symptoms are dominated by dry, unproductive cough and more or less severe dyspnea, which is not necessarily closely related to the size of the irradiated lung volume. Dyspnea, thus, is a very characteristic sign of the acute inflammation phase of radiation pneumopathy. Because it can be easily measured, it also serves as a common response criterion in animal experiments of radiation-induced lung damage.

The radiologic picture of lung fibrosis is characterized by contracted, dense scar tissue that occupies a much smaller volume than the originally irradiated volume and is surrounded by hypodense volumes indicating compensatory emphysema. The clinical symptoms are dominated by dyspnea and may also include signs of right heart failure secondary to pulmonary hypertension.

Histopathologically, radiation pneumopathy is characterized by the focal infiltration of inflammatory cells into the pulmonary interstitium, which is associated, right from the beginning, with the deposition of intercellular matrix material, leading finally to the destruction of the alveolar histoarchitecture. The focal nature of histopathologic changes is remarkable in view of the random nature of energy deposition and cell inactivation by radiation; however, similar nonrandom damage development has been described in other irradiated tissues such as the spinal cord (2) and heart (3).

The alveolar epithelium consists of type I and type II epithelial cells in an almost balanced numeric proportion. Type I cells cover approximately 90% of the alveolar surface and type II pneumocytes represent the replicator precursors of type I cells. In normal steady state, the turnover time of the alveolar epithelium is approximately 4–5 weeks. After toxic injury, the alveolar surface is denuded because of the high vulnerability of the flat type I epithelial cells and proliferation of type II pneumocytes may accelerate more than 10-fold (4), with a great number of cytokines, growth factors, and cyclins regulating this response. Over the course of several days, type II pneumocyte proliferation results in alveolar reepithelialization. The immediate proliferative reaction of type II cells after injury may be the key event in the sufficient restoration of the alveolar epithelial surface. For this reason, agents, such as the herbicide paraquat, the antineoplastic drug bleomycin and, naturally, radiation, that are toxic to both type I and type II cells or which inhibit type II cell proliferation preferentially induce the irreversible reaction leading to pulmonary fibrosis (4).