The role of PARC in pulmonary inflammation
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Smoking causes inflammation of the airways. Symptoms range from chronic smoker’s cough to worsening of asthma to gradual destruction of the pulmonary structures, which ultimately makes it impossible to breathe. Much of the damage in this process is done by white blood cells, in particular a specific type of white blood cell, called macrophage (Greek for ‘big eater’) that is attracted into the lung of smokers in increased numbers. The specific function of macrophages is to engulf bacteria and foreign particles such as contained in smoke and to digest them. For this purpose they release enzymes that chew up proteins, oxidants that kill bacteria and other proteins that attract more white blood cells. However, in excess these compounds start to destroy the fine structures of the lung. Macrophages, which can live for several months derive from circulating monocytes. Monocytes are produced in the bone marrow from where they are sent on their voyage through the vasculature. Once circulating they can live for only a few days. A small fraction of these monocytes will adhere to the vessel wall and emigrate to the different tissues, where they become the much longer-lived macrophages, while the majority of monocytes, which do not lodge anywhere, are programmed to die. Certain stimuli can increase the fraction of cells that survive, adhere to the vessel wall and develop into macrophages. Specifically, a family of proteins called chemokines signals to circulating white blood cells to emigrate into the lung or other tissues. Some of these chemokines are produced throughout the body, others are more locally expressed by a specific organ. PARC – the abbreviation stands for ‘pulmonary and activation regulated chemokine’ – is primarily made by the lung. We recently found that cultured monocytes migrate toward a source of PARC. As these cells develop into macrophages, they stop reacting to PARC, but instead produce it, thus creating a vicious cycle. Since there are more macrophages in the lungs of smokers, the question arises, whether cigarette smoke causes increased production of PARC by cells of the lung, and whether this leads to increase of monocyte/macrophage accumulation in the lungs. 
 
 
 
 
 
 
 
 To examine whether PARC plays a role in the inflammatory response to cigarette smoke in the lungs, we will 1) determine whether fluid obtained from the lungs of smokers contain higher concentrations of PARC. 2) We then ask, how PARC may cause an increased accumulation of macrophages in the lung. For this purpose we will determine whether PARC increases the adhesion of monocytes to endothelial cells, the cells that line the vascular tree. Next we will determine, whether PARC enhances migration of monocytes through the layer of endothelial cells. Since increased macrophage numbers can also be caused by an increased survival rate of monocytes, we will then ask if PARC can increase monocyte survival. Finally we will determine, whether stimulation with PARC causes increased production of inflammatory mediators that can attract yet more white blood cells to the lung. Since the receptor for PARC, which we recently recognized, is also expressed by endothelial cells, which line the vascular tree, and by fibroblasts, which form the connective lung tissue, we will also determine in 3) the effect of PARC on these cells. In endothelial cells we are mostly interested, whether PARC makes them more adhesive for while blood cells and whether there form gaps between the endothelial cells, which make it easier for the monocytes to transmigrate. If PARC plays a role in macrophage accumulation and in enzyme release in the lungs of smokers, inhibition of PARC may represent a target for future therapeutic intervention.