DOI: 10.25549/usctheses-c40-350071
title: RAS-modification as a novel therapy for pulmonary indications in T2D

description: Introduction. Patients with type 2 diabetes mellitus (T2DM) are not only prone to lung infections, the severity of the infection is also likely to be exacerbated. This increase in pulmonary disease may be due to immune impairment and structural abnormalities caused by T2DM-induced oxidative stress (OS) and chronic inflammation. Among many factors that contribute to development and progression of diabetic complications is A-II. Activation of pathological arm of renin-angiotensin system (RAS) results in increased levels of A-II and signaling through AT1 receptor. This pathway is well recognized for its role in induction of OS, inflammation, hypertrophy and fibrosis. New therapeutic targets are needed that consider both immune and structural components of lung health. RAS-modifying therapies that opposes the actions of A-II can result in the amelioration of diabetic complications; enhancing the overall welfare of diabetic patients. In this thesis, the effect of RAS modification by A(1-7) treatment, in the db/db mouse model of T2DM, was investigated. Specifically, the impact on the pulmonary architecture and the innate response to pulmonary infection. In order to further validate the validity of targeting RAS as potential therapeutic we used a de-identified insurance claims dataset to look at the association between RAS-modifying medications and the incidence of pulmonary complications. ❧ Methods. For the animal studies, 8 week old mice were treated with either saline (htz and db/db) or A(1-7) (htz and db/db) for up to 16 weeks. Histology and CT scans were used to look structural changes in the lung as well as possible mechanisms for variations observed. Assays were conducted to assess innate immune function prior to infection followed by challenge with intra-tracheal administration of different doses of S. aureus. For the patient data, a retrospective analysis was conducted using claims data from a US commercial insurance company (2007-2013). The study consisted of patients with an emerging HTN diagnosis. We used Cox and OLS analysis in 2 Models to look at the effect of ACE-Is and ARBs in this population. The events included pneumonia and influenza (infectious), COPD and allied conditions (inflammatory), and other diseases (structural). ❧ Results. Treatment with A(1-7) reduced levels of circulating proinflammatory cytokines that contribute to the low grade inflammation observed in diabetes. In addition, lung pathologies associated with T2DM, including fibrosis and congestion, were decreased with treatment. OS and macrophage infiltration were also reduced in the lungs after treatment with A(1-7). Although there was a low bacterial burden 24hrs after infection, the saline-treated db/db mice were most likely to have detectable levels of S. aureus in the lung. Ex vivo assays revealed a decrease in neutrophil phagocytosis and activation in diabetic animals, and A(1-7) treatment restored innate-immune function. Analysis of myeloid bone marrow progenitors showed a reduction in db/db mice that was also reversed by A(1-7) treatment. A total of 215,215 patients were followed in the patient study. These corresponded into three groups depending on the first prescribed anti-hypertension medication; ACE-Is (47.21%), ARBs (11.40%) and CCBs/Diuretics-Control (41.39%). The use of ACE-I as first treatment significantly reduced the incidence of infectious, inflammatory and structural outcomes in 2 models; it also increased the time (delayed) to diagnosis with prolonged treatment. Primary ARB use only significantly lowered the incidence of structural diagnoses; prolonged treatment did reduce incidence of all three diagnosis groups and significantly delayed disease onset. ❧ Conclusions. Long-term administration of A(1-7) to db/db mice is effective in prevention of progression of lung disease in db/db mice. Treatment prevented pathological remodeling of the tissues and reduced OS, fibrosis and inflammation. These results also suggest diabetes adversely affected innate immune function and A(1-7) treatment reversed or prevented these effects. ACE-Is and ARBs delay the progression of pulmonary complications in vulnerable populations. Research into the RAS may harvest future therapies for patients with potential chronic pulmonary conditions. Overall, RAS-modification may be a viable therapeutic target to treat diabetic complications and improve the life of patients with T2DM.