Rhesus theta-defensin prevents death in a mouse model of severe acute respiratory syndrome coronavirus pulmonary disease.

We evaluated the efficacy of rhesus theta-defensin 1 (RTD-1), a novel cyclic antimicrobial peptide, as a prophylactic antiviral in a mouse model of severe acute respiratory syndrome (SARS) coronavirus (CoV) lung disease. BALB/c mice exposed to a mouse-adapted strain of SARS-CoV demonstrated 100% survival and modest reductions in lung pathology without reductions in virus titer when treated with two intranasal doses of RTD-1, while mortality in untreated mice was approximately 75%. RTD-1-treated, SARS-CoV-infected mice displayed altered lung tissue cytokine responses 2 and 4 days postinfection compared to those of untreated animals, suggesting that one possible mechanism of action for RTD-1 is immunomodulatory.

Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.

Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer-small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery.

Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis.

The release of reactive oxygen species (ROS) and cytokines by alveolar macrophages has been demonstrated in asbestos-induced pulmonary fibrosis, but the mechanism linking alveolar macrophages to the pathogenesis is not known. The GTPase Rac1 is a second messenger that plays an important role in host defense. In this study, we demonstrate that Rac1 null mice are protected from asbestos-induced pulmonary fibrosis, as determined by histological and biochemical analysis.

Protective and pathologic roles of the immune response to mouse hepatitis virus type 1: implications for severe acute respiratory syndrome.

Intranasal mouse hepatitis virus type 1 (MHV-1) infection of mice induces lung pathology similar to that observed in severe acute respiratory syndrome (SARS) patients. However, the severity of MHV-1-induced pulmonary disease varies among mouse strains, and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS.

Toll-like receptor 4 deficiency increases disease and mortality after mouse hepatitis virus type 1 infection of susceptible C3H mice.

Severe acute respiratory syndrome (SARS) is characterized by substantial acute pulmonary inflammation with a high mortality rate. Despite the identification of SARS coronavirus (SARS-CoV) as the etiologic agent of SARS, a thorough understanding of the underlying disease pathogenesis has been hampered by the lack of a suitable animal model that recapitulates the human disease. Intranasal (i.

Fetal exposure to ethanol has long-term effects on the severity of influenza virus infections.

Alcohol use by pregnant women is a significant public health issue despite well-described risks to the fetus including physical and intellectual growth retardation and malformations. Although clinical studies are limited, they suggest that in utero alcohol exposure also results in significant immune deficiencies in naive neonates. However, little is known about fetal alcohol exposure (FAE) effects on adult infections.

Apoptosis is differentially regulated by burn severity and dermal location.

Background: The cellular processes that contribute to cell death in burns are poorly understood. This study evaluated the distribution and extent of apoptosis in an established rat model of acute dermal burn injury.

Materials And Methods: A branding iron (100 degrees C) was applied to the depilated dorsum of seven rats, creating burn contact times of 1-8, 10, 12, and 14 s.

Alcian Blue and Pyronine Y histochemical stains permit assessment of multiple parameters in pulmonary disease models.

Utilization of a combined Alcian Blue and Pyronine Y histochemical method for the assessment of multiple parameters in the respiratory tract of various species is described. Acidic mucins were deep blue (sialylated mucins), red (sulfated mucins), or variably purple (mixture of sialylated/sulfated mucins), and differential mucus production was readily detected in a murine respiratory syncytial virus vaccine model of pulmonary inflammation. Elastic fibers stained red in the walls of pulmonary arteries, connecting airways, alveolar septa, and subpleural interstitium.

Morphological parameters for assessment of burn severity in an acute burn injury rat model.

Determination of burn severity (i.e. burn depth) is important for effective medical management and treatment.

Gene profiling studies in the neonatal ovine lung show enhancing effects of VEGF on the immune response.

Preterm and young neonates have an increased predisposition to respiratory distress syndrome (RDS) associated with an immature development of lung surfactant. Glucocorticoids (GCs) are the major immunomodulatory agents used to increase lung development and reduce the mortality and morbidity of preterm infants with RDS. However, their safety remains uncertain, and the precise mechanisms by which they improve lung function are unclear.

Comparison of histochemical methods for murine eosinophil detection in an RSV vaccine-enhanced inflammation model.

A comparative study of histochemical detection of eosinophils in fixed murine tissue is lacking. Five histochemical methods previously reported for eosinophil detection were quantitatively and qualitatively compared in an established murine RSV vaccine-enhanced inflammation model. Nonspecific neutrophil staining was evaluated in tissue sections of neutrophilic soft tissue lesions and bone marrow from respective animals.

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs.

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles.

Murine pancreatic duct ligation induces stress kinase activation, acute pancreatitis, and acute lung injury.

Background: Acute lung injury is a major determinant of outcomes in acute pancreatitis. We evaluated acute lung injury and stress kinase activation in ligation-induced acute pancreatitis in mice.

Methods: Mice with duct ligation or sham operation were killed after 24 or 48 hours.

Chronic alcohol consumption increases the severity of murine influenza virus infections.

Respiratory infections with both seasonal as well as potential pandemic Influenza viruses represent a significant burden on human health. Furthermore, viruses such as Influenza are increasingly recognized as important etiologic agents in community acquired pneumonia. Within the U.

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.

Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ.

The porcine lung as a potential model for cystic fibrosis.

Airway disease currently causes most of the morbidity and mortality in patients with cystic fibrosis (CF). However, understanding the pathogenesis of CF lung disease and developing novel therapeutic strategies have been hampered by the limitations of current models. Although the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) has been targeted in mice, CF mice fail to develop lung or pancreatic disease like that in humans.

Teaching medical pathology in the twenty-first century: virtual microscopy applications.

Virtual microscopy (VM) has been implemented and evaluated in the histology and general and systemic pathology courses at the University of Iowa Carver College of Medicine. Advantages of VM over traditional microscopy include accessibility and efficiency of learning and the ability to integrate VM with computer-assisted interactive learning. Advantages of using VM as opposed to digital photomicrographs include the ability to pan and zoom, explore the slide, and make independent observations.

IL-13 is required for eosinophil entry into the lung during respiratory syncytial virus vaccine-enhanced disease.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in children. Children previously vaccinated with a formalin-inactivated RSV vaccine experienced enhanced morbidity and mortality upon natural RSV infection. Histological analysis revealed the presence of eosinophils in the pulmonary infiltrate of the vaccinated children.

Differential role of gamma interferon in inhibiting pulmonary eosinophilia and exacerbating systemic disease in fusion protein-immunized mice undergoing challenge infection with respiratory syncytial virus.

Secondary exposure to respiratory syncytial virus (RSV) can lead to immunopathology and enhanced disease in vaccinated individuals. Vaccination with individual RSV proteins influences the type of secondary RSV-specific immune response that develops upon challenge RSV infection, as well as the extent of immunopathology. RSV-specific memory CD4 T cells can directly contribute to immunopathology through their cytokine production.

Surfactant-associated protein A provides critical immunoprotection in neonatal mice.

The collectins surfactant-associated protein A (SP-A) and SP-D are components of innate immunity that are present before birth. Both proteins bind pathogens and assist in clearing infection. The significance of SP-A and SP-D as components of the neonatal immune system has not been investigated.

Morphologic characterization of early ligation-induced acute pancreatitis in rats.

Background: Bile-pancreatic duct ligation in rats causes acute pancreatic inflammation. We performed serial morphologic evaluation of the exocrine pancreas after duct ligation to facilitate further investigations using the model.

Methods: The pancreas was excised from 74 rats after 0, 1, 3, 5, 24 or 48 hours of duct ligation or sham surgery.

Maternal alcohol ingestion reduces surfactant protein A expression by preterm fetal lung epithelia.

In addition to neurodevelopmental effects, alcohol consumption at high levels during pregnancy is associated with immunomodulation and premature birth. Premature birth, in turn, is associated with increased susceptibility to various infectious agents such as respiratory syncytial virus (RSV). The initial line of pulmonary innate defense includes the mucociliary apparatus, which expels microorganisms trapped within the airway secretions.

Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosis.

Damage-specific DNA-binding (DDB) protein heterodimer has been extensively studied in the context of nucleotide excision repair. However, the smaller subunit, DDB2, is also implicated in tumor suppressor p53-mediated processes, although the precise details of the DDB2 - p53 interactions are unknown. Here, we report that Ddb2(-/-) and Ddb2(+/-) mice have shortened lifespans and increased frequency and spectrum of spontaneous tumors.

Pretreatment with recombinant human vascular endothelial growth factor reduces virus replication and inflammation in a perinatal lamb model of respiratory syncytial virus infection.

Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. Preterm and young infants are at increased risk for pulmonary immaturity characterized by insufficient surfactant production as well as increased risk for severe manifestations of respiratory syncytial virus (RSV) infection. Innate immune components including surfactant proteins A and D, and beta-defensins have putative antimicrobial activity against pulmonary pathogens including RSV.

Neonatal ovine pulmonary dendritic cells support bovine respiratory syncytial virus replication with enhanced interleukin (IL)-4 And IL-10 gene transcripts.

The lung microenvironment is constantly exposed to microorganisms and particulate matter. Lung dendritic cells (DCs) play a crucial role in the uptake and processing of antigens found within the respiratory tract. Respiratory syncytial virus (RSV) is a common respiratory tract pathogen in children that induces an influx of DCs to the mucosal surfaces of the lung.