Acute pulmonary embolism (PE) is the third leading cause of cardiovascular death in the United States. Moderate to severe PE can cause pulmonary arterial hypertension (PH) with resultant right ventricular (RV) heart damage. The mechanisms leading to RV failure after PE are not well defined, although it is becoming clear that PH-induced inflammatory responses are involved. We previously demonstrated profound neutrophil-mediated inflammation and RV dysfunction during PE that was associated with increased expression of several chemokine genes. However, a complete assessment of transcriptional changes in RVs during PE is still lacking. We have now used DNA microarrays to assess the alterations in gene expression in RV tissue during acute PE/PH in rats. Key results were confirmed with real-time RT-PCR. Nine CC-chemokine genes (CCL-2, -3, -4, -6, -7, -9, -17, -20, -27), five CXC-chemokine genes (CXCL-1, -2, -9, -10, -16), and the receptors CCR1 and CXCR4 were upregulated after 18 h of moderate PE, while one C-chemokine (XCL-1) and one CXC-chemokine (CXCL-12) were downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated increased expression of many inflammatory genes. There was also a major shift in the expression of components of metabolic pathways, including downregulation of fatty acid transporters and oxidative enzymes, a change in glucose transporters, and upregulation of stretch-sensing and hypoxia-inducible transcription factors. This pattern suggests an extensive shift in cardiac physiology favoring the expression of the "fetal gene program."

Study Objectives: Recent work has suggested that rats from the Copenhagen strain may express a pro-thrombotic phenotype. We compared the physiologic responses of Copenhagen (COP) and Sprague Dawley (SD) rats in our experimental model of autologous clot pulmonary embolism (ACPE).

ABSTRACT: Transgenic and knockout mice usefully model the mechanisms that result in the clearance of Cryptosporidium parvum from the gut. CD4 + cells, cells expressing MHC class II, and CD154/CD40 interactions are essential. Unexpectedly, AND RAG‐/‐ and DO11.10 RAG‐/‐ mice with single specificities of T cells successfully clear Cryptosporidium infection. Clearance is accompanied by activation of CD4 + cells in the MLN. The ability of T cells bearing receptors for apparently irrelevant and non‐cross reactive antigens to activate and to clear infection is surprising. The requirement for class II MHC expression for Cryptosporidium clearance raises the alternative possibilities that (a) class II MHC is required to present a peptide that is loaded as a consequence of infection or (b) that the cytokine environment engendered by a Cryptosporidium infection allows affinity for self MHC to activate nahe T cells. In order to test the hypothesis that peptide loading is necessary, we used ApEα‐/‐Ii‐/‐ mice that express a hybrid IA‐IE MHC molecule. They also carry a transgene that makes an Ea peptide while disruption of their invariant chain blocks the loading of a foreign peptide on to their MHC class II molecules. After oral gavage, the course of infection was followed by ELISA. CD4 + cells in the MLN of these mice were activated to express CD69 and the infection was cleared. We conclude that the loading of a Cryptosporidium or other infection‐dependent peptide onto the MHC class II molecules of APCs is not necessary for clearance of Cryptosporidium. Instead the TcR affinity for self‐MHC must suffice for T cell activation in the cytokine environment resulting from infection