Neutrophils Mediate Pulmonary Artery Thrombosis In Situ.

Pulmonary embolism is a life-threatening condition, which can result in respiratory insufficiency and death. Blood clots occluding branches of the pulmonary artery (PA) are traditionally considered to originate from thrombi in deep veins (usually in legs). However, growing evidence suggests that occlusion of the vessels in the lungs can develop without preceding deep vein thrombosis (DVT). In this work, we used an inferior vena cava (IVC) complete ligation model of DVT in Wistar rats to explore the possibility and mechanisms of PA thrombosis under the conditions where all routes of thrombotic mass migration from peripheral veins are blocked. We demonstrate that rats both with normal and reduced neutrophil counts developed thrombi in the IVC, although, neutropenia caused a substantial decrease in thrombus size and a shift from fresh fibrin toward mature fibrin and connective tissue inside the thrombus. Massive fibrin deposition was found in the PA branches in the majority of DVT rats with normal neutrophil counts, but in none of the neutropenic animals. Neutrophil ablation also abolished macroscopic signs of lung damage. Altogether, the results demonstrate that thrombi in the lung vasculature can form in situ by mechanisms that require local neutrophil recruitment taking place in the DVT setting.

Pulmonary Artery Thrombosis: A Diagnosis That Strives for Its Independence.

According to a widespread theory, thrombotic masses are not formed in the pulmonary artery (PA) but result from migration of blood clots from the venous system. This concept has prevailed in clinical practice for more than a century. However, a new technologic era has brought forth more diagnostic possibilities, and it has been shown that thrombotic masses in the PA could, in many cases, be found without any obvious source of emboli. Chronic obstructive pulmonary disease, asthma, sickle cell anemia, emergency and elective surgery, viral pneumonia, and other conditions could be complicated by PA thrombosis development without concomitant deep vein thrombosis (DVT). Different pathologies have different causes for local PA thrombotic process. As evidenced by experimental results and clinical observations, endothelial and platelet activation are the crucial mechanisms of this process. Endothelial dysfunction can impair antithrombotic function of the arterial wall through downregulation of endothelial nitric oxide synthase (eNOS) or via stimulation of adhesion receptor expression. Hypoxia, proinflammatory cytokines, or genetic mutations may underlie the procoagulant phenotype of the PA endothelium. Both endotheliocytes and platelets could be activated by protease mediated receptor (PAR)- and receptors for advanced glycation end (RAGE)-dependent mechanisms. Hypoxia, in particular induced by high altitudes, could play a role in thrombotic complications as a trigger of platelet activity. In this review, we discuss potential mechanisms of PA thrombosis in situ.

Mast cell accumulation precedes tissue fibrosis induced by intravenously administered amorphous silica nanoparticles.

Despite the increasing use of amorphous silica nanoparticles (SNPs) in biomedical applications, their toxicity after intravenous administration remains a major concern. We investigated the effects of single 7 mg/kg intravenous infusions of 13 nm SNPs on hemodynamic parameters in rats. Hematological and biochemical parameters were assessed at 7, 30, and 60 d post treatment. Silicon content in the liver, lungs, heart, and kidney was analyzed, as well as tissue histology with special emphasis on mast cell (MC) content. SNP infusion had no effect on hemodynamics, nor did it alter hematological or biochemical parameters. SNP retention in the liver was conspicuous for up to 60 d. Among the other organs analyzed, silicon content was significantly increased only in the lung at 1-h post infusion. Despite the relatively low dose, SNP administration caused extensive liver remodeling, including the formation of multiple foreign body-type granulomas starting 7 d post treatment, and subsequent development of fibrosis. Histopathological changes in the liver were not preceded by hepatocyte necrosis. We found increased MC abundance in the liver, lungs, and heart starting on day 30 post treatment. MC recruitment in the liver preceded fibrosis, suggesting that MCs are involved in liver tissue remodeling elicited by intravenously administered SNPs.