Inflammation: The role of the lung and neutrophil margination

Severe inflammation is characterized by a systemic inflammatory response, which if persistent can lead to inflammatory complications. The inflammatory response is associated with, amongst others, a rapid increase in blood and tissue neutrophils and induction of the acute phase protein fibrinogen. Neutrophils are important effector cells of the innate immune system. Aberrant activation of these cells has been associated with tissue damage in persistent inflammation. In systemic inflammation firstly, neutrophils become primed (or pre-activated) which dramatically increases their sensitivity for activation by inflammatory mediators. This priming phenotype is particularly relevant for adhesion associated functions. This phenotype causes problems when neutrophils encounter additional inflammatory stimuli resulting in excessive adhesion and enhanced cytotoxic functions. The lung in particular is an organ where neutrophils are prone to receive this second stimulus. This is due to the large and narrow (smaller than diameter of neutrophils) microvascular bed in which neutrophils exhibit a long transit time. This is because of the need of deformation of the cells in order to pass through these narrow vessels. Primed neutrophils, however, have impaired deformability, which leads to excessive margination (i.e. neutrophils get stuck in the lung). These marginated neutrophils are prone to activation by signals originating from lung tissue and or lung vascular endothelium.

Activated neutrophil binding soluble fibrinogen

Activated neutrophils use integrins such as MAC-1 (CD11b/CD18) to adhere to vascular endothelium under conditions of blood flow, which precedes migration into the tissues. Activated neutrophils adhering to vascular endothelium can cause endothelial damage through degranulation and release of free oxygen radicals. After transendothelial migration into the lung parenchyma the activated cells can cause tissue damage. Neutrophils utilize integrins for firm adhesion and transendothelial migration in post-capillary venules in basically all tissues in the body. The lung, however, is an exception because of the narrow architecture of the capillaries. Others have shown that homing of granulocytes into the lung can be independent of integrins. This depends on the stimulus (strain of bacteria, sterile inflammation). Therefore, there are at least two types of neutrophil adhesion 1) integrin dependent and 2) integrin independent adhesion.

Apart from a rapid increase in peripheral neutrophil counts, systemic inflammation is accompanied by an elevation of plasma soluble fibrinogen (sFib) by enhanced production by the liver. This acute phase protein increases in the peripheral blood from around 2-3 mg/ml (normal homeostasis) up to 10mg/ml (under inflammatory conditions). Fibrinogen is an important constituent of the coagulation system. However, the increase in fibrinogen concentration during inflammation is not considered relevant for the clotting capacity under these conditions. It has been shown by others that fibrinogen plays a role in modulating neutrophil adhesion. We will focus on the role of fibrinogen in modulating the integrin independent adhesion in the lung.

Fibrinogen molecule, Flick et al.

This project will focus on
1)The role of the lung (neutrophil margination) in modulating peripheral blood neutrophil phenotypes
2) Modulating neutrophil margination and adhesion and the role of fibrinogen in this process

For more information you can contact:

Janesh Pillay MD