Studies On The Risk Factors Of Sensitization Caused By Traditional Chinese Medicine And The Sensitized Components Of Chinese Medicine Products

With the increasing applications of Traditional Chinese Medicine (TCM) in clinical treatments, the safety issues of Chinese medicine products (CMP), especially the sensitization induced by Traditional Chinese Medicine Injectables (TCMIs), raise more attentions among the clinicians. The social effects associated with adverse reactions of individual TCM initiated concerns among the public, even some misunderstanding about the safety of CMP, which put forward severe challenges on toxicological studies of TCM. Currently, studies related to clinical safety of CMP are relatively insufficient, such as scarce knowledges about risk factors of sensitization induced by TCM, ineffective methods to evaluate the sensitizations preclinically, and unavailablity of systematic screening of sensitized components of TCM, which significantly hampers the process to improve the quality of CMP, and even influences the developments of modern TCM industry. Therefore, screening and evaluation of the sensitized components of CMP (especially TCMIs) has become an important task in the TCM-related research fields, several key scientific questions to be addressed are the following:1. What are the risk factors of sensitization induced by TCM?2. How to extract valuable information from massive literature data, therefore elucidating the underlying mechanisms from these isolated knowledges, and eventually identifying suspicious sensitized components of TCM?3. How to establish reliable animal models to evaluate the sensitization of TCMIs administered intravenously?4. How to identify the sensitized components of CMP?Among these important scientific questions, I focus on the risk factors of sensitization induced by TCM and sensitized components of CMP in this study. The network pharmacology technology was applied to construct the network model of TCM allergen for the first time. The significant risk factors and potentially sensitized components of TCM were found through this method. Furthermore, an animal model was established for the evaluation of sensitization induced by TCMIs administered intravenously. Chlorogenic acid was used as the test compound to demonstrate the reliability of this model. The main findings and academic contributions of this study are listed below:1. Retrospective review of literatures indicated that allergic history, dosage forms, routes of administration, solvents, drug combination are the major risk factors of TCM to trigger sensitization. TCMIs is the main dosage form of TCM to induce sesitization that are linked with serious adverse reactions such as anaphylactic shock. Furthermore, the allergic history, routes of administration, solvents, and the time point for the first appearance after injections are significantly associated with the risk of anaphylactic shock induced by TCMIs. In current work, a retrospective review method was utilized to systemically analyze the reports about sensitization induced TCM. Results of this study uncovered the major risk factors invovled in sensitization of TCMIs, which also provides reliable experimental information for screening and evaluation of the sensitized components of TCM.2. Analysis on the TCM allergen network suggested that several TCMs could easily induce sensitizations clinically, such as honeysuckle, scutellaria, forsythia, and gardenia, etc. And gardenia, houttuynial, as well as isatidis, were the herbs with high risk to induce anaphylatic shock. Furthermore, beta-sitosterol, chlorogenic acid, and palmitic acid were highly correlated with sensitizations induced by TCM. The network pharmacology technology was used to construct the network model of TCM allergen for the first time, which provides valuble information about potential mechanisms of sensitization and makes it possible to identify potential sensitized components of TCM. This work demonstrated a new avenue to investigate the toxicology of TCM.3. Results from animal studies indicated that current animal model showed good sensitivity and specificity for the evaluation of the sensitization through intravenous administration. Through this model, positive compounds would significantly promote the PLN proliferation and induce TNP-specific AFCs formation, while none of these reactions were observed for negative compounds. In addition, the types of T cell differentiations in sensitization may also be distinguished by PLN parameters. In the present study, a mouse model for screening and evaluation of the sensitized components of TCM was established, which provides a new way to evaluate the sensitization of TCMIs experimentally.4. Chlorogenic acid was evaluated by the animal model and results indicated that chlorogenic acids can significantly induce sensitization. And there are structure-activity relationships between structural characteristics of these compounds and the intensity and types of sensitization. The current work provided convincing experimental evidence for the sensitization induced by chlorogenic acid through intravenous administration.5. A potential sensitized mechanism of chorogenic acid was proposed. Several lines of experimental data indicated that this compound induced a Th2type sensitization probably through the covalent interactions with macromolecules to form a complete antigen, which then stimulated the DCs maturation to launch antigen-presenting, and promoted the expression of Tim4in DCs to break the immune tolerance balance of Treg cells. Based on these results, altered immune balances mediated by Treg cell might be the important molecular mechanism for the sensitization induced by chlorogenic acid, which provided important experimental evidence to elucidate the mechanisms of sensitization induced by chlorogenic acid.