There is a great amount of evidence for the presence of alternatively activated M2 macrophages in asthmatic allergic inflammation. Our published studies indicated that the macrophage is necessary for asthmatic inflammation. Despite ample reports showing that the alveolar macrophages of asthmatics express different cell surface markers and unique patterns of gene expression, the mechanism of phenotypic transformation of the macrophage to the M2 phenotype, along with its cellular functions involved in asthma pathogenesis, are not fully elucidated.
In aim 1, using both the human SBP-AG protocol and a comparable mouse model, we will precisely measure macrophage trafficking and population shifts of alveolar macrophage in acute allergic inflammation. We reported a rapid development of chemotactic gradient for macrophages and the appearance of newly recruited alveolar macrophages in acute allergic inflammation. We will examine if blocking of monocyte recruitment attenuates allergic inflammation.
In aim 2, we will investigate CSF-1 as a key regulator for M2 macrophage transformation, and interrogate our recently reported ATX-LPA pathway as a CSF-dependent effector product of M2 macrophages in allergic airway inflammation. Autotaxin (ATX) and its enzymatic product, lysophosphatidic acid (LPA), play a pivotal role in the pathogenesis of asthma, and alternatively activated macrophages are potential main sources of ATX protein in the asthmatic lung. We will investigate the mechanism for regulating ATX and LPA production in macrophage by employing novel cell specific targeted knock-out mice.
In aim 3, we will investigate biochemical pathways of LPA production in allergic lung inflammation, focusing on PLA2 group 7, which is a candidate enzyme that produces lysophosphatidyl choline (LPC). Although ATX action on LPC was identified as the final step of the enzymatic pathway of LPA production, production of LPC from corresponding phosphatidylcholine (PC) is yet to be defined. Our supporting data strongly suggested that macrophage produced PLA2 group 7 is a strong candidate for the reaction, and could be a target for therapeutic intervention. The proposed study would lead to a better understanding of pathogenesis of asthma, which will eventually improve management of asthma.
Asthma has been a major healthcare burden to patients, families and our society for decades. However, despite advances in the understanding of asthma, the management of asthma is far less than ideal, which leads to a huge loss in the patient's economical and educational opportunities This proposed study will examine the details of the cellular and biochemical steps of our newly proposed mechanism, specifically focusing on alveolar macrophage cells which are likely to be responsible for the chronic refractory asthma. The proposed study could lead to a better understanding of the pathogenesis of asthma, which will eventually improve management of asthma.