Megakaryocytes participate in the occurrence of bleomycin-induced pulmonary fibrosis

Abstract

Megakaryocytes are normally present in the lung where they play a role in platelet homeostasis. The latter are well known to participate in the pathogenesis of lung damage, particularly in acute lung injury. Although megakaryocytes are usually not mentioned as a characteristic histopathologic nding associated to acute pulmonary injury, a few studies point out that their number is increased in the lungs of patients with diffuse alveolar damage. In this autopsy study we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute respiratory distress syndrome. We have studied pulmonary tissue samples of 18 patients most of which died after prolonged disease and use of mechanical ventilation. Most samples showed broproliferative or brotic diffuse alveolar damage and an increased number of megakaryocytes. In six, thrombi of the pulmonary microcirculation were seen. We compare our ndings with previous published autopsy reports, mainly focusing on the description of megakaryocytes. Our patients showed abnormal coagulation parameters with high levels of brinogen, D-dimers and variable thrombocytopenia. Since the lung is considered an active site of megakariopoiesis, a prothrombotic status leading to platelet activation, aggregation and consumption may trigger a compensatory pulmonary response. An increased number of pulmonary megakaryocytes suggests and supports a relation with the thrombotic events so often seen in COVID-19. Regardless of its etiology, future studies of patients dying with acute pulmonary injury should include pulmonary megakaryocytes as a histologic variable of interest.

Hematopoietic and Lung Platelet Biogenesis as a Prognostic Indicator in Idiopathic Pulmonary Fibrosis (IPF)

“…The finding that the IPF lung transcriptome is less enriched with megakaryocyte gene signature than controls is intriguing. This seems to contradict a previous report that CD41+ megakaryocyte counts are increased in lung tissue of bleomycin-challenged mice (10), possibly reflecting the fact that the bleomycin-induced pulmonary fibrosis mouse model is not able to fully recapitulate human IPF. Our finding suggests a possibility that that IPF lungs harbor fewer (healthy) megakaryocytes due to their altered megakaryocyte niche (i.e., IPF lungs provide a less optimal niche for megakaryocytes) and that megakaryocytes (especially extravascular/interstitial megakaryocytes) are actually decreased in IPF lungs.…”

“…One possibility is that decreased megakaryocyte/platelet biogenesis in IPF lungs induces megakaryocyte/platelet biogenesis in bone marrow. For example, bone marrow may be producing more megakaryocytes and/or releasing more megakaryocytes into the circulation in response to factors released by fibrotic lungs (e.g., CXCL12 (10)) (Figure 10). The second possibility is that megakaryocytes cannot stay in the altered niche within IPF lungs and therefore escape into the circulation.…”

“…Whether the observed decrease in megakaryocyte gene signature in IPF lung and increase in a megakaryocyte signature in IPF blood is the consequence or the cause of pulmonary fibrosis is currently unknown. A previous study with a bleomycin-induced pulmonary fibrosis mouse model suggested that megakaryocytes migrate to injured lung tissue partially through the CXCL12/CXCR4 axis and contribute to fibrogenesis by promoting the proliferation and trans-differentiation of fibroblasts through direct contact and TGF-β1 signaling (10). However, a more recent study reported that megakaryocyte/platelet-specific TGF-β1 conditional knockout mice (PF4-Cre, TGF-β1 floxed mice) were not protected against bleomycin-induced pulmonary fibrosis (21).…”

Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature

“…MKs produce transforming growth factor-beta and participate in bone marrow fibrosis [49]. A similar pro-fibrotic capacity has been demonstrated for pulmonary MKs in an experimental model of lung fibrosis [50]. Precisely, diffuse lung fibrosis is one of the greatest complications of ARDS.…”

Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage. An autopsy study with clinical correlation and review of the literature.

“…MKs produce transforming growth factor-beta and participate in bone marrow brosis [49]. A similar pro-brotic capacity has been demonstrated for pulmonary MKs in an experimental model of lung brosis [50]. Precisely, diffuse lung brosis is one of the greatest complications of ARDS.…”