Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury

BACKGROUND: Individuals with deficiencies of pulmonary surfactant protein C (SP-C) develop interstitial lung disease (ILD) that is exacerbated by viral infections including respiratory syncytial virus (RSV). SP-C gene targeted mice (Sftpc -/-) lack SP-C, develop an ILD-like disease and are susceptible to infection with RSV. METHODS: In order to determine requirements for correction of RSV induced injury we have generated compound transgenic mice where SP-C expression can be induced on the Sftpc -/- background (SP-C/Sftpc -/-) by the administration of doxycycline (dox). The pattern of induced SP-C expression was determined by immunohistochemistry and processing by Western blot analysis. Tissue and cellular inflammation was measured following RSV infection and the RSV-induced cytokine response of isolated Sftpc +/+ and -/- type II cells determined. RESULTS: After 5 days of dox administration transgene SP-C mRNA expression was detected by RT-PCR in the lungs of two independent lines of bitransgenic SP-C/Sftpc -/- mice (lines 55.3 and 54.2). ProSP-C was expressed in the lung, and mature SP-C was detected by Western blot analysis of the lavage fluid from both lines of SP-C/Sftpc -/- mice. Induced SP-C expression was localized to alveolar type II cells by immunostaining with an antibody to proSP-C. Line 55.3 SP-C/Sftpc -/- mice were maintained on or off dox for 7 days and infected with 2.6x10(7) RSV pfu. On day 3 post RSV infection total inflammatory cell counts were reduced in the lavage of dox treated 55.3 SP-C/Sftpc -/- mice (p = 0.004). The percentage of neutrophils was reduced (p = 0.05). The viral titers of lung homogenates from dox treated 55.3 SP-C/Sftpc -/- mice were decreased relative to 55.3 SP-C/Sftpc -/- mice without dox (p = 0.01). The cytokine response of Sftpc -/- type II cells to RSV was increased over that of Sftpc +/+ cells. CONCLUSIONS: Transgenic restoration of SP-C reduced inflammation and improved viral clearance in the lungs of SP-C deficient mice. The loss of SP-C in alveolar type II cells compromises their response to infection. These findings show that the restoration of SP-C in Sftpc -/- mice in response to RSV infection is a useful model to determine parameters for therapeutic intervention

Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc−/−) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc−/− mice. Sftpc+/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc+/+ and Sftpc−/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc−/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF

Building connectomes using diffusion MRI: why, how and but

Why has diffusion MRI become a principal modality for mapping connectomes in vivo? How do different image acquisition parameters, fiber tracking algorithms and other methodological choices affect connectome estimation? What are the main factors that dictate the success and failure of connectome reconstruction? These are some of the key questions that we aim to address in this review. We provide an overview of the key methods that can be used to estimate the nodes and edges of macroscale connectomes, and we discuss open problems and inherent limitations. We argue that diffusion MRI-based connectome mapping methods are still in their infancy and caution against blind application of deep white matter tractography due to the challenges inherent to connectome reconstruction. We review a number of studies that provide evidence of useful microstructural and network properties that can be extracted in various independent and biologically-relevant contexts. Finally, we highlight some of the key deficiencies of current macroscale connectome mapping methodologies and motivate future developments

Pathogenesis of Interstitial Lung Disease in Children and Adults

Interstitial lung diseases (ILDs) occur across the lifespan, from birth to advanced age. However, the causes, clinical manifestations, histopathology, and management of ILD differ greatly among infants, older children, and adults. The historical approach of classifying childhood ILD (chILD) using adult classification schemes may therefore have done more harm than good. Nevertheless, identification of novel forms of chILD in the past decade, such as surfactant metabolism dysfunction disorders and neuroendocrine cell hyperplasia of infancy (NEHI), as well as genomic analysis of adult ILDs, has taught us that identical genotypes may result in distinct phenotypes at different ages and developmental stages, and that lung developmental pathways and cellular phenotypes are often recapitulated in adult ILDs. Thus comparison of the pathophysiology of ILD in children and adults in the context of lung development is useful in understanding the pathogenesis of these disorders, and may lead to novel therapeutic interventions for ILDs at all ages

A steady-state model reconstruction of the patagonian ice sheet during the last glacial maximum

During the Last Glacial Maximum (LGM), the Patagonian Ice Sheet (PIS) was the largest Quaternary ice mass in the Southern Hemisphere outside of Antarctica. Although the margins of the LGM ice sheet are now well established through end-moraine mapping and dating, apart from a few modelling and empirical studies, there remains a lack of constraint on its thickness and three-dimensional configuration. Here, we provide a high-resolution steady-state model reconstruction of the PIS at its maximum - LGM - extent applied using Nye's perfect-plastic ice rheology. The yield-strength parameter for the perfect-plastic flow model was calibrated against independent empirical reconstructions of the Lago Pueyrredón Glacier, where the former vertical extent of this major outlet glacier is well constrained by cosmogenically-dated trimlines and lateral and end-moraine limits. Using this derived yield-strength parameter, the perfect-plastic model is then applied to multiple flowlines demarking each outlet across the entirety of the PIS in a GIS framework. Our results reveal that the area of the PIS was ∼504,500 km2 (±8.5%) with a corresponding modelled ice volume of ∼554,500 km3 (±10%), equivalent to ∼1.38 m (±10%) of eustatic sea-level lowering at the LGM. Maximum surface elevation was at least 3500m asl although the majority of the ice sheet surface was below 2500 m asl. We find that our ice sheet reconstruction is in good general agreement with previous estimates of net PIS volume derived from transient modelling studies. We attribute the slightly lower aspect-ratio of our ice sheet (and its concomitant 5% reduction in volume and sea-level equivalent) to the lower yield strength applied, based on more temperate and dynamic ice sheet conditions

A steady-state model reconstruction of the patagonian ice sheet during the last glacial maximum

Abstract During the Last Glacial Maximum (LGM), the Patagonian Ice Sheet (PIS) was the largest Quaternary ice mass in the Southern Hemisphere outside of Antarctica. Although the margins of the LGM ice sheet are now well established through end-moraine mapping and dating, apart from a few modelling and empirical studies, there remains a lack of constraint on its thickness and three-dimensional configuration. Here, we provide a high-resolution steady-state model reconstruction of the PIS at its maximum - LGM - extent applied using Nye’s perfect-plastic ice rheology. The yield-strength parameter for the perfect-plastic flow model was calibrated against independent empirical reconstructions of the Lago Pueyrredón Glacier, where the former vertical extent of this major outlet glacier is well constrained by cosmogenically-dated trimlines and lateral and end-moraine limits. Using this derived yield-strength parameter, the perfect-plastic model is then applied to multiple flowlines demarking each outlet across the entirety of the PIS in a GIS framework. Our results reveal that the area of the PIS was ∼504,500 km² (±8.5%) with a corresponding modelled ice volume of ∼554,500 km³ (±10%), equivalent to ∼1.38 m (±10%) of eustatic sea-level lowering at the LGM. Maximum surface elevation was at least 3500m asl although the majority of the ice sheet surface was below 2500 m asl. We find that our ice sheet reconstruction is in good general agreement with previous estimates of net PIS volume derived from transient modelling studies. We attribute the slightly lower aspect-ratio of our ice sheet (and its concomitant 5% reduction in volume and sea-level equivalent) to the lower yield strength applied, based on more temperate and dynamic ice sheet conditions