Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models.

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Platelets and Multi-Organ Failure in Sepsis.

The lung is the organ with the highest vascular density in the human body. It is therefore perceivable that the endothelium of the lung contributes significantly to the circulation of extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies. In addition to the endothelium, EVs may arise from alveolar macrophages, fibroblasts and epithelial cells. Because EVs harbor cargo molecules, such as miRNA, mRNA, and proteins, these intercellular communicators provide important insight into the health and disease condition of donor cells and may serve as useful biomarkers of lung disease processes. This comprehensive review focuses on what is currently known about the role of EVs as markers and mediators of lung pathologies including COPD, pulmonary hypertension, asthma, lung cancer and ALI/ARDS. We also explore the role EVs can potentially serve as therapeutics for these lung diseases when released from healthy progenitor cells, such as mesenchymal stem cells.

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Extracellular vesicles: novel communicators in lung diseases.

CONTEXT: Idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (HP) are diffuse parenchymal lung diseases characterized by a mixture of inflammation and fibrosis, leading to lung destruction and finally death. AIMS: The aim of this study was to compare different pathophysiological mechanisms, such as angiogenesis, coagulation, fibrosis, tissue repair, inflammation, epithelial damage, oxidative stress, and matrix remodeling, in both disorders using bronchoalveolar lavage (BAL). METHODS: At diagnosis, patients underwent bronchoscopy with BAL and were divided into three groups: Control (n = 10), HP (n = 11), and IPF (n = 11), based on multidisciplinary approach (clinical examination, radiology, and histology): Multiplex searchlight technology was used to analyze 25 proteins representative for different pathophysiological processes: Eotaxin, basic fibroblast growth factor (FGFb), fibronectin, hepatocyte growth factor (HGF), interleukine (IL)-8, IL-12p40, IL-17, IL-23, monocyte chemotactic protein (MCP-1), macrophage-derived chemokine (MDC), myeloperoxidase (MPO), matrix metalloproteinase (MMP)-8, MMP-9, active plasminogen activating inhibitor 1 (PAI-1), pulmonary activation regulated chemokine (PARC), placental growth factor (PlGF), protein-C, receptor for advanced glycation end products (RAGE), regulated on activation normal T cells expressed and secreted (RANTES), surfactant protein-C (SP-C), transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue factor, thymic stromal lymphopoietin (TSLP), and vascular endothelial growth factor (VEGF). RESULTS: All patients suffered from decreased pulmonary function and abnormal BAL cell differential compared with control. Protein levels were increased in both IPF and HP for MMP-8 (P = 0.022), MMP-9 (P = 0.0020), MCP-1 (P = 0.0006), MDC (P = 0.0048), IL-8 (P = 0.013), MPO (P = 0.019), and protein-C (P = 0.0087), whereas VEGF was decreased (P = 0.0003) compared with control. HGF was upregulated in HP (P = 0.0089) and active PAI-1 was upregulated (P = 0.019) in IPF compared with control. Differences in expression between IPF and HP were observed for IL-12p40 (P = 0.0093) and TGF-β1 (P = 0.0045). CONCLUSIONS: Using BAL, we demonstrated not only expected similarities but also important differences in both disorders, many related to the innate immunity. These findings provide new clues for further research in both disorders.

Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis (vol 8, pg 38, 2013)

Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung condition associated with significant morbidity and mortality. Unfortunately, the current treatment for this disease is mainly supportive. Mesenchymal stem cells (MSCs) due to their immunomodulatory properties are increasingly being studied for the treatment of ARDS and have shown promise in multiple animal studies. The therapeutic effects of MSCs are exerted in part in a paracrine manner by releasing extracellular vesicles (EVs), rather than local engraftment. MSC-derived EVs are emerging as potential alternatives to MSC therapy in ARDS. In this review, we will introduce EVs and briefly discuss current data on EVs and MSCs in ARDS. We will discuss current literature on the role of MSC-derived EVs in pathogenesis and treatment of ARDS and their potential as a treatment strategy in the future.

Mesenchymal stem cells-derived extracellular vesicles in acute respiratory distress syndrome: a review of current literature and potential future treatment options.

Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures that carry important intercellular communication mechanisms, allowing targeted transfer of diverse biologic cargo, including protein, mRNA, and microRNA, among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges that need to be overcome before EVs can also be used as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.

Extracellular Vesicles: A New Frontier for Research in Acute Respiratory Distress Syndrome.

This study was conducted to investigate the effect of intratracheal and intravenous administration of microparticles (MPs) on developing acute respiratory distress syndrome (ARDS). The blood MPs from lipopolysaccharide-treated rats were collected and examined by transmission electron microscopy (TEM). Cellular source of the MPs was identified by fluorescent-labeled antibodies after the circulating MPs were delivered to naive rats. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 productions in bronchoalveolar lavage fluid (BALF) and plasma were determined 24 h after the rats received intratracheal and intravenous administration of the MPs. Histopathologic examination of lungs was performed by light microscope. A TEM image of MPs showed spherical particles at a variable diameter from 0.1 to 0.5 µm. Endothelial- and leukocyte-derived vesicles were abundant in the investigated samples. Treatment with MPs may lead to significant increases in MPO, TNF-α, IL-1β, and...

Administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome

The aim of this study was to evaluate the effect and underlying mechanism of Yangyinqingfei decoction on radiation-induced lung injury in rats. Wistar rats (n=75) were randomly divided into five experimental groups (A-E). Rats in two of the groups were administered saline solution, whereas rats in the remaining three groups were administered different doses of Yangyinqingfei decoction. After one week, the rats were irradiated with a single dose of 25 Gy to their right hemi-thoraxes by a 60Co γ-ray, with the exception of the control group, which underwent sham irradiation. The effect of Yangyinqingfei decoction was assessed one, two and four weeks post-irradiation according to the pathological changes and the right lung index (wet weight of right lung/body weight ×100%). Expression levels of matrix metalloproteinase-12 (MMP-12) and tissue inhibitors of metalloproteinases-1 (TIMP-1) in lung tissue were determined using the reverse transcription-polymerase chain reaction and western blot analysis. Pretreatment with Yangyinqingfei resulted in a significant dose-dependent resistance to radiation-induced body weight loss. The expression of MMP-12 and TIMP-1 increased following irradiation. However, the levels of MMP-12 and TIMP-1 in groups receiving Yangyinqingfei were lower four weeks after irradiation compared with those in rats administered saline. Cumulatively, these results suggest that Yangyinqingfei has a protective effect on radiation-induced lung injury in rats, possibly by downregulating MMP-12 and TIMP-1 expression.

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Effect of Yangyinqingfei decoction on radiation‑induced lung injury via downregulation of MMP12 and TIMP‑1 expression

Objective: To investigate the alterations of microparticles in acute respiratory distress syndrome (ARDS) in rats. Methods: 18 Wistar male rats were randomly divided into three groups: no intervention, sham (saline control) group and ARDS group (LPS induced). Blood was collected from abdominal aorta and microparticles were extracted through multiple rounds of centrifugation. Particles were analyzed by flow cytometry and transmission electron microscope. Results: The circulating concentration of total microparticles of rats with ARDS induced by lipopolysaccharide (LPS) did not change compared with other two groups. However, ARDS rats expressed higher concentration of leukocyte- and endothelium- derived microparticles in the three groups. Conclusion: Our results indicate that leukocyte and endothelial cell-derived particles may play an important role in ARDS. Thus it is important not only to monitor total microparticle levels but also the phenotypes, which may contribute to the prevention and early treatment of ARDS.

Isolation and phenotypic characteristics of microparticles in acute respiratory distress syndrome.

Simvastatin attenuates acute lung injury by activation of A2B adenosine receptor.

* Equal contributors. Received December 8, 2014; Accepted February 3, 2015; Epub February 1, 2015; Published February 15, 2015 Abstract: Objective: To investigate the alterations of microparticles in acute respiratory distress syndrome (ARDS) in rats. Methods: 18 Wistar male rats were randomly divided into three groups: no intervention, sham (saline control) group and ARDS group (LPS induced). Blood was collected from abdominal aorta and microparticles were extracted through multiple rounds of centrifugation. Particles were analyzed by flow cytometry and transmission electron microscope. Results: The circulating concentration of total microparticles of rats with ARDS induced by lipopolysac- charide (LPS) did not change compared with other two groups. However, ARDS rats expressed higher concentration of leukocyte- and endothelium- derived microparticles in the three groups. Conclusion: Our results indicate that leukocyte and endothelial cell-derived particles may play an important role in ARDS. Thus it is important not only to monitor total microparticle levels but also the phenotypes, which may contribute to the prevention and early treat- ment of ARDS.

Shaohua Cai

Papers

Administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome

Effect of Yangyinqingfei decoction on radiation‑induced lung injury via downregulation of MMP12 and TIMP‑1 expression

Isolation and phenotypic characteristics of microparticles in acute respiratory distress syndrome.

Simvastatin attenuates acute lung injury by activation of A2B adenosine receptor.

Original Article Isolation and phenotypic characteristics of microparticles in acute respiratory distress syndrome