Respiratory mechanics, lung structure and inflammation of the TIMP3 knockout mouse during its response to lung insults.

摘要

Matrix metalloproteinases (MMPs) are enzymes that degrade the extracellular matrix (ECM), which are regulated by the tissue inhibitors of metal loprotemases (TIMPS). MMPs and TIMPs work in a balance to ensure proper tissue turnover within the lungs thereby maintaining optimal lung function. An MMP/TIMP imbalance resulting in excessive ECM breakdown has been reported to be associated with several pulmonary diseases. However it remains unclear if the MMP/TIMP imbalance contributes to the development or progression of these diseases. To address this issue this thesis has utilized the TIMP3 knockout mouse, which possesses an MMP/TIMP imbalance resulting in an emphysema-like phenotype of air-space enlargement and decreased lung function. These mice were challenged by exposure to different lung insults. The governing hypothesis was that the TIMP3 null lung will have an altered response to different lung insults due to its MMP/TIMP imbalance and altered lung structure.;The primary finding of this thesis was that the TIMP3 null mice developed a rapid increase in lung compliance following septic insults, but not in response to mechanical ventilation or hyperoxic exposure. This increase in pulmonary compliance developed over only six hours following two different models of systemic sepsis, and was dependent on the presence of alveolar macrophages. Alterations to the ECM, including breakdown of collagen and fibronectin, were observed in the septic TIMP3 null mice, which may contribute to these observed compliance alterations. Furthermore, these studies indicated that MMP2, 8, 9, and various inflammatory cytokines and chemokines were not responsible for these changes. However, MMP7 was attenuated following macrophage depletion, suggesting it may be involved in the development of increased compliance during the septic response of the TIMP3 null lung.;From this work we conclude that TIMP3, in combination with the alveolar macrophage, plays and integral role in the lung during its response to a septic insult.;To test this hypothesis, TIMP3 knockout and wild-type mice were exposed to systemic sepsis, mechanical ventilation and hyperoxia. Following each insult respiratory mechanics were assessed and correlated to changes in lung structure, MMPs abundance and concentrations of inflammatory cytokines and chemokines.