Platelets in lung biology

Abstract

Platelets and the lungs have an intimate relationship. Platelets are anucleate mammalian blood cells that continuously circulate through pulmonary vessels and that have major effector activities in hemostasis and inflammation. The lungs are reservoirs for megakaryocytes, the requisite precursor cell in thrombopoiesis, which is the intricate process by which platelets are generated. Platelets contribute to basal barrier integrity of the alveolar capillaries, which selectively restricts the transfer of water, proteins, and red blood cells out of the vessels. Platelets also contribute to pulmonary vascular repair. Although platelets bolster hemostatic and inflammatory defense of the healthy lung, experimental evidence and clinical evidence indicate that these blood cells are effectors of injury in a variety of pulmonary disorders and syndromes. Newly discovered biological capacities of platelets are being explored in the context of lung defense, disease, and remodeling.

Figure 1

Thrombopoiesis. (a) Cellular intermediates in thrombopoiesis. See text and Reference for further details. (b) Photomicrographs of human cells involved in thrombopoiesis. The photographs are from different experiments and at different magnifications and do not precisely illustrate relative cellular sizes. (Left to right) CD34⁺ hematopoietic stem cell (HSC) precursors stained for integrin subunit α_IIb; CD34+HSC-derived megakaryocyte stained for a_IIb and spliceosome factors; CD34+HSC-derived megakaryocyte extending proplatelets, stained for mammalian target of rapamycin; freshly isolated platelets—both elongate platelets undergoing fission and resting discoid platelets—from venous blood stained for actin. See References , , and for further details. Reprinted with permission from References , , and . (c) Electron micrographs of human platelets undergoing fission. See Reference for further details. Reprinted with permission from Reference .

Figure 2

Blood cell retention in lungs. The majority of megakaryocytes that reach the lungs appear to be retained in capillaries and arterioles (see Figure 3). Polymorphonuclear leukocytes (PMN) transit through pulmonary capillaries but must deform, and their transit times are delayed compared with those of red blood cells, creating a substantial marginated pool. Most mature platelets readily pass through alveolar capillaries. Transit of released proplatelets (see Figure 1) has not been characterized. See text and Reference for further details. Diameters of human megakaryocytes, megakaryocyte precursors, and platelets are from References , , and .[Megakaryocyte and platelet diameters are smaller in mice (32).] Human PMN and capillary diameters are from Reference .

Figure 3

Lung megakaryocytes. Megakaryocytes are found in human lung microvessels and may spawn platelets and platelet precursors in this location. Megakaryocyte nuclei with little or no cytoplasm are also detected in microvessels in human lungs. The process of platelet biogenesis from proplatelet extensions and released proplatelets has, however, not been formally demonstrated in the lungs of humans or experimental animals.

Figure 4

Platelets stabilize pulmonary vascular endothelial barriers. (a) Under basal conditions, platelets express and/or release stabilizing factors that interact with receptors on alveolar capillary endothelial cells. Sphingosine-1-phosphate is a prototype stabilizing factor. Receptors for stabilizing factors are linked to intracellular signaling pathways that regulate cytoskeletal interactions, adherens junction assembly, and basal endothelial barrier properties. Homophilic binding of vascular endothelial cell cadherin (VE-cadherin) is central to stable alveolar capillary endothelial barrier function (reviewed in References and 83). (b) Animal models show that in severe thrombocytopenia, basal alveolar capillary endothelial barrier function is disrupted, leading to increased permeability and transvascular escape of water, solutes, and red blood cells (RBC) (reviewed in Reference 64). Large arrows denote fluid exiting to the alveolar space, and small arrows denote fluid exiting to the interstitial space and to the lymph.

Figure 5

Platelets contribute to alveolar capillary membrane injury and increased-permeability lung edema in ALI/ARDS. On the basis of clinical observations and studies in experimental models, activated platelets mediate ALI by mechanisms that include aggregation, the release of mediators, signaling of endothelial cells, and interactions with polymorphonuclear leukocytes (PMN) and monocytes, triggering or amplifying inflammatory damage (reviewed in References –, , and 103).