Elsevier

Vascular Pharmacology

Volume 49, Issues 4–6, October–December 2008, Pages 141-150
Vascular Pharmacology

Review
Endothelium–platelet interactions in inflammatory lung disease

https://doi.org/10.1016/j.vph.2008.06.004Get rights and content

Abstract

In addition to their established role in hemostasis, recent studies have identified platelets as key regulators of inflammatory reactions. Upon activation, platelets interact with both endothelial cells and circulating leukocytes. By receptor-mediated activation of interacting cell types and by release of mitogenic, pro-inflammatory and -coagulatory mediators, platelets contribute crucially to the initiation and propagation of pathological conditions and processes such as inflammatory bowel disease or atherosclerosis. In inflammatory lung disease, platelets play a critical role in the recruitment of neutrophils, eosinophils and lymphocytes as shown in experimental models of acute lung injury and allergic airway inflammation. Circulating platelet–leukocyte aggregates have been detected in patients with allergic asthma and cystic fibrosis, and in experimental lung injury. Here, we discuss the molecular mechanisms regulating the interaction of platelets with leukocytes, endothelial cells, and the subendothelial matrix with special regard to platelet kinetics in pulmonary microvessels and the putative role of platelets in inflammatory lung disorders. In light of the existing data from experimental and clinical studies it is conceivable that platelet adhesion molecules and platelet mediators provide promising targets for novel therapeutic strategies in inflammatory lung diseases.

Introduction

Platelets are anucleated fragments of bone marrow megakaryocytes of approximately 2–4 μm in diameter. Since most of the common cytoplasmic organelles, including mitochondria, components of the Golgi apparatus, the endoplasmic reticulum, and ribosomes are present in platelets, the platelet can be regarded as a structure potentially capable of all cellular functions except those immediately dependent on the nucleus (Han and Baker, 1964). Daily production of ~ 2.5 × 1011 cells with a median life span of 7–9 days constitutes a total platelet pool of ~ 2 × 1012 cells in human adults. Platelets contain at least three types of morphologically different granules, i.e. α-granules, dense granules, and lysosomes (Fig. 1). Within these granules, platelets store a variety of bioactive substances including growth factors, cytokines, chemokines, nucleotides, biogenic amines, adhesion molecules, and coagulation factors (Warkentin et al., 2003, Zarbock et al., 2007). The key role of platelets in the initiation and realization of effective primary hemostasis and thrombosis has long been established (Marcus and Safier, 1993) and is attributable to their ability to bind extracellular matrix proteins and soluble ligands with a variety of surface adhesion molecules. More recently, platelets have been identified as modulators and mediators of inflammatory reactions. By interacting with microvascular endothelial cells, adherent and circulating leukocytes or both, platelets may play a critical role in the initiation and propagation of inflammatory lung diseases. Inhibition of platelet adhesion and activation or blocking of platelet-dependent mediators with clinically established or novel pharmaceutical interventions may thus present new therapeutic strategies for the prevention or treatment of lung inflammatory disorders. Here, we outline the mechanisms by which platelets interact with extracellular matrix and plasma proteins, leukocytes and in particular with endothelial cells, and review clinical and experimental data which implicate these mechanisms in the pathophysiology of inflammatory lung disease.

Section snippets

Platelet adhesion to the injured vessel wall

Platelet adhesion to the subendothelial matrix and subsequent platelet aggregation are essential to limit blood loss at sites of vascular injury. Surface expression of various adhesion molecules enables platelets to interact with extracellular matrix proteins either via direct ligand–receptor interaction or indirectly via soluble ligands (Fig. 2). Direct binding of platelets to extracellular collagen at sites of vascular injury is mediated via several glycoproteins (GPs). GPIa/IIa, also known

Platelet–endothelial cell interaction

In addition to interacting with extracellular matrix proteins and soluble ligands, platelets can also directly adhere to the vascular endothelium. In the intact human vascular system, ~ 1012–1013 endothelial cells weighing not more than 110 g cover a comparatively large surface area of approximately 350 m2 (Pries and Kuebler, 2006). Hence in healthy human adults the numbers of circulating platelets and resident endothelial cells are roughly similar. Under physiological conditions, platelets

Platelet kinetics in the lung

By an indicator dilution technique using radiolabeled blood cells, Doerschuk et al. (1990) determined the margination of monocytes, neutrophils, lymphocytes and platelets within the microvasculature of various organs (Doerschuk et al., 1990). Ten minutes after central venous injection of the radiolabeled cells, a relatively large percentage of neutrophils but only few platelets had remained in the lung (Fig. 4). Thus, while neutrophils were found to have a large marginated pool residing in the

Platelets in inflammatory lung disease

The recognition that platelets not only interact with extracellular matrix proteins, but also with endothelial and – as we discuss later – with inflammatory cells and their potential to release chemokines and other inflammatory cytokines has led to their implication in a variety of inflammatory conditions (Tan et al., 2004, Wagner and Burger, 2003, Weyrich et al., 2003). Platelets interact rapidly with both Gram-positive and Gram-negative bacteria via bridging molecules which bind to platelet

Conclusions

By recognition of their ability to interact both with endothelial cells and various leukocyte subsets, a critical role for platelets in the initiation and propagation of lung inflammatory diseases has arisen. Further insights into the mechanisms that trigger platelet activation in acid-induced lung injury, cystic fibrosis and allergic asthma are required to allow for a better understanding of the initial inflammatory response. Recent data also suggest a pathogenic role for platelet–endothelial

Acknowledgments

We thank Michael Mertens for editorial assistance. Presented work from our own group was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) Ku1218/4 and Ku1218/5 to W.M. Kuebler and by a fellowship of the Kaiserin-Friedrich Foundation Berlin to A. Tabuchi.

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