Post acute phase of ionizing radiation (IR), survivors face two unavoidable challenges: IRpneumonitis in months and lung fibrosis in years. The unique characteristic of IR-induced lung damage is itsendless sterile inflammation cascade. IR pneumonitis progress into lung fibrosis, an irreversible lost of lungfunction that can greatly reduce the quality of life and eventually cost life. Currently, there is no drug forblocking the progression of this devastating disease. The underlying mechanism for this long-lasting pathological process is unclear, however, some factsare clear: 1) there are no infection pathogens; 2) it is a long-lasting inflammation process (months-years); 3)it becomes worsen with times, until fibrosis has formed and organ function is destroyed; 4) the IR lung tissueis the target of immune reaction; and 5) immune suppressors (steroids) are effective but transient and cannot be used in a long run. These facts strongly suggest that the immune reaction play a major role in theprogression of IR pneumonitis and lung fibrosis. Based on this concept, we have been searching for anti-immune agents to mitigate the IR lung injuryfor 4 years and found that triptolide (TPL, MW 360, purified from the traditional medicinal herb Tripterygiumwilfordii Hook F) reduces both IR pneumonitis and lung fibrosis as evidenced by: 1) At the acute phase, whenTPL was given orally for 2 days at a dose of 0.25 mg/kg/daily after 15 Gy thorax IR, it reduced the numberof lymphocytes in the BALF (bronchial alveolar lavage fluid), the lung infiltrated inflammatory cells andexudates and MPO (myeloperoxidase) activity, the plasma pro-inflammation cytokines, such as IL1 , TNF ,lymphotaxin, IL6, ICAM-1, P-selectin, and plasma SP-D (surfactant protein D, released due to IR lungdamage); 2) At the sub-acute phase, the use of TPL (0.25 mg/kg orally, qod for 17 days) reduced theseverity of pneumonitis, as evidenced by fewer infiltration cells in both BALF and lung, and a reducedplasma SP-D, lymphotaxin, IL6, ICAM-1, IL15, P-selectin, etc; 3) At late phase, the use of TPL (0.25 mg/kgqod or q3d for 3-6 months) reduced the severity of lung fibrosis at 7-12 months as evidenced by improvedlung function (lower respiratory rate and higher lung compliance), reduced lung fibrosis (low density in conebeam CT scan, less fibrosis in H&E and Trichrome staining), decreased hydroxyproline content and reducedIL1a, IL6 and ICAM-1 in lung tissue; and 4) The therapeutic dose of TPL for 3-6 months was well tolerated. Based on the mitigation data and its stable and easy to use, we hypothesize that TPL is an effectivemitigator for IR pneumonitis and lung fibrosis. To maximize the TPL beneficial effect, we will focus on thefollowing aims: 1) To define the optimal dose, starting time, and schedule for utilizing TPL to mitigate IRpneumonitis; 2) To determine the optimal schedule for IR lung fibrosis. This project is likely to develop TPL as an effective mitigator of IR pneumonitis and lung fibrosis formass nuclear casualty. It will also be of benefit to lung cancer patients with radiotherapy.
This proposal is to determine the optimal dose; starting time and schedule for the maximumefficacy of triptolide (a small; stable and oral use) in mitigation of IR pneumonitis and lung fibrosis inmass casualty settings. It will also be of benefit to lung cancer patients with radiotherapy.
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