Platelets: a critical link between inflammation and microvascular dysfunction

Abstract

Inflammation is an underlying feature of a variety of human diseases. An important manifestation of this pathophysiological response is microvascular dysfunction, which includes the activation of vascular endothelial cells, and circulating leucocytes and platelets. While endothelial cells and leucocytes are widely accepted as critical players in the microvascular alterations induced by inflammation, recent attention has focused on the modulatory role of platelets, which act both as effector and target cells in inflamed microvessels. Evidence is presented to demonstrate the capacity for 'cross-talk' between platelets and other cells (endothelial cells, leucocytes) that contribute to an inflammatory response, and to illustrate the pathophysiological consequences of these interactions of platelets with other cells within the microvasculature.

Figure 1. A schematic diagram of the ‘cross-talk’ between platelets, vascular endothelium and leucocytes in response to stimuli released during inflammatory conditions

The arrows indicate the direction of the communication, and illustrate both the physical interactions (via cell adhesion molecules, such as P-selectin) and soluble factors (e.g. chemokines, cytokines, etc.) that mediate the cell–cell communication via autocrine and paracrine pathways. Some of the pathological changes resulting from this platelet ‘cross-talk’ are listed below the endothelial cells and leucocytes, and above the platelets. The information portrayed here is discussed throughout the text. AA: arachidonic acid; LTB₄: leukotriene B₄.

Figure 2. A proposed schematic of the opposing roles of platelets in endothelial barrier function

Platelets maintain normal barrier function through the release of soluble factors, most likely proteins, or lipid mediators such as sphingosine-1-phosphate (S1P). However under inflammatory conditions, this protective function of platelets may be overcome. Vascular permeability (P) may be initially increased in a platelet-independent manner, allowing platelet accumulation on the subendothelial matrix. These platelets may become activated and release factors that act directly, or indirectly via recruitment of leucocytes, to further disrupt the barrier function. This latter pathway is mediated via a burst of ROS generation from the leucocytes