Inflammatory Regulation by Circulating Haptoglobin 2-2 in the Severity of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive airflow limitation that is not fully reversible. COPD is a highly complex inflammatory disease involving systemic inflammation and manifestations, currently lacking effective treatment to modify its progression and to decrease mortality. Systemic inflammation indicated by an increase in plasma levels of various inflammatory proteins and acute phase reactants, which belong to different biological pathways in COPD, are significantly associated with the disease severity. Haptoglobin (Hp) is an acute protein, which is synthesized in the liver, lung epithelial cells, and alveolar macrophages. The level of plasma Hp is increased in response to different kind of inflammatory stimuli including injuries, infections, and stress. The lungs are a major site of the extrahepatic synthesis of Hp, and this protein protects the lungs against inflammatory agents and lung injuries. The deficiency of Hp leads to lung tissue destruction due to the decreased natural bactericidal activities for the reduction of recruited neutrophils, eventually leading to the development of emphysema and COPD. In humans, Hp has three main phenotypes including Hp1-1, Hp2-1, and Hp2-2. Accumulated studies showed that there are functional differences between different Hp phenotypes, for example, Hp2-2 phenotype is a weaker antioxidant compared to Hp1-1 or Hp2-1. However, in our preliminary data, we demonstrated that Hp2-2 has an exclusively high association with COPD severity and the level of several inflammatory mediators. In addition, many studies reported that Hp has the regulatory potential in immune and inflammatory responses. Therefore, we postulate that, in COPD, Hp2-2 is prominent in contributing inflammatory environment through regulating associated immune cells. To test our hypothesis, we propose to investigate Hp2-2, paralleled with the other phenotypes, in mediating COPD pathogenesis. Also, we aimed to identify novel inflammatory-associated RNA species and proteins in regard to disease severity and Hp levels.This is a 3-year project with 3 specific aims: (1) to investigate the potential functions of specific Hp phenotypes in the regulation of COPD progression from clinical samples; (2) to verify specific Hp phenotype mediated inflammatory responses in COPD animal models and the evaluation of therapeutic efficacy; (3) to investigate the cellular and molecular mechanisms of specific Hp phenotype in regulating immune responses in severe COPD. We will explore the molecular mechanisms underlying specific Hp phenotype mediated circulating RNAs or proteins after inflammatory stimulation. This study will not only extend our knowledge into the mechanism whereby specific Hp phenotype is implicated in abnormal inflammation, pulmonary injury and repair but will also provide potential therapeutic targets for the treatment of COPD