Aging exacerbates damage and delays repair of alveolar epithelia following influenza viral pneumonia

Background

Influenza virus infection causes significantly higher levels of morbidity and mortality in the elderly. Studies have shown that impaired immunity in the elderly contributes to the increased susceptibility to influenza virus infection, however, how aging affects the lung tissue damage and repair has not been completely elucidated.

Methods

Aged (16–18 months old) and young (2–3 months old) mice were infected with influenza virus intratracheally. Body weight and mortality were monitored. Different days after infection, lung sections were stained to estimate the overall lung tissue damage and for club cells, pro-SPC⁺ bronchiolar epithelial cells, alveolar type I and II cells to quantify their frequencies using automated image analysis algorithms.

Results

Following influenza infection, aged mice lose more weight and die from otherwise sub-lethal influenza infection in young mice. Although there is no difference in damage and regeneration of club cells between the young and the aged mice, damage to alveolar type I and II cells (AT1s and AT2s) is exacerbated, and regeneration of AT2s and their precursors (pro-SPC-positive bronchiolar epithelial cells) is significantly delayed in the aged mice. We further show that oseltamivir treatment reduces virus load and lung damage, and promotes pulmonary recovery from infection in the aged mice.

Conclusions

These findings show that aging increases susceptibility of the distal lung epithelium to influenza infection and delays the emergence of pro-SPC positive progenitor cells during the repair process. Our findings also shed light on possible approaches to enhance the clinical management of severe influenza pneumonia in the elderly.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0116-z) contains supplementary material, which is available to authorized users.     

Fluid–structure interaction in a fully coupled three-dimensional mitral–atrium–pulmonary model

This paper aims to investigate detailed mechanical interactions between the pulmonary haemodynamics and left heart function in pathophysiological situations (e.g. atrial fibrillation and acute mitral regurgitation). This is achieved by developing a complex computational framework for a coupled pulmonary circulation, left atrium and mitral valve model. The left atrium and mitral valve are modelled with physiologically realistic three-dimensional geometries, fibre-reinforced hyperelastic materials and fluid–structure interaction, and the pulmonary vessels are modelled as one-dimensional network ended with structured trees, with specified vessel geometries and wall material properties. This new coupled model reveals some interesting results which could be of diagnostic values. For example, the wave propagation through the pulmonary vasculature can lead to different arrival times for the second systolic flow wave (S2 wave) among the pulmonary veins, forming vortex rings inside the left atrium. In the case of acute mitral regurgitation, the left atrium experiences an increased energy dissipation and pressure elevation. The pulmonary veins can experience increased wave intensities, reversal flow during systole and increased early-diastolic flow wave (D wave), which in turn causes an additional flow wave across the mitral valve (L wave), as well as a reversal flow at the left atrial appendage orifice. In the case of atrial fibrillation, we show that the loss of active contraction is associated with a slower flow inside the left atrial appendage and disappearances of the late-diastole atrial reversal wave (AR wave) and the first systolic wave (S1 wave) in pulmonary veins. The haemodynamic changes along the pulmonary vessel trees on different scales from microscopic vessels to the main pulmonary artery can all be captured in this model. The work promises a potential in quantifying disease progression and medical treatments of various pulmonary diseases such as the pulmonary hypertension due to a left heart dysfunction.

     

Reconstruction of the hand in Apert syndrome: a simplified approach

Children born with Apert acrocephalosyndactyly pose great challenges to the pediatric hand surgeon. Reconstructive dilemmas consist of shortened, deviated phalanges and extensive skin deficits following syndactyly release. We present a 10-year review of patients with Apert acrocephalosyndactyly who were treated with a simplified surgical approach. Between 1986 and 1996, 10 patients with Apert syndrome underwent reconstructive surgery of their hands. The overall strategy involved early bilateral separation of syndactylous border digits at 1 year of age, followed by sequential unilateral middle syndactyly mass separation with thumb osteotomy and bone grafting as needed. In these 10 patients, a total of 53 web spaces were released, 49 of which involved osteotomies for complex syndactyly. Only local flaps and full-thickness skin grafts from the groin were used in all cases to achieve soft-tissue coverage. To date, seven of the 53 web spaces have needed revision (revision rate, 13 percent). Eleven thumb osteotomies (nine opening wedge and two closing wedge) were performed. Bone grafts from the proximal ulna or from other digits were used in all cases. To date, none of these thumb osteotomies have needed revision. This early, simplified approach to the complex hand anomalies of Apert acrocephalosyndactyly has been successful in achieving low revision rates and excellent functional outcomes as measured by gross grasp and pinch and by patient and parent satisfaction.     

EGF-like peptide of Dictyostelium discoideum is not a chemoattractant but it does restore folate-mediated chemotaxis in the presence of signal transduction inhibitors

A synthetic EGF-like (EGFL) peptide (DdEGFL1), equivalent to the first EGFL domain in the extracellular matrix protein CyrA, has previously been shown to enhance random cell motility and cAMP-mediated chemotaxis in Dictyostelium discoideum. However the role of DdEGFL1 as a potential chemoattractant had not been addressed. In this study, a micropipette assay and an under-agarose migration assay showed that DdEGFL1 is not a chemoattractant for Dictyostelium cells. A radial bioassay was used to show that DdEGFL1 does not significantly enhance folate-mediated chemotaxis in contrast to its chemokinetic effect during chemotaxis toward cAMP. However, DdEGFL1 was able to rescue chemotaxis toward folate when the pathway was inhibited by pharmacological agents that inhibit known components of the signaling cascade (e.g. phosphatidylinositol 3-kinase, phospholipase A2, tyrosine kinases, and calmodulin). These data suggest that DdEGFL1 may activate a novel motility pathway that when coupled with folic acid receptor activation, can maintain the normal migratory response to folic acid in vegetative cells. Together, this data provides new insight into the function of EGFL repeats during Dictyostelium chemotaxis and the existence of a novel motility pathway regulated by EGFL peptides and/or repeats in this model organism.     

Development of a 3D finite element model of lens microcirculation

Background

It has been proposed that in the absence of a blood supply, the ocular lens operates an internal microcirculation system. This system delivers nutrients, removes waste products and maintains ionic homeostasis in the lens. The microcirculation is generated by spatial differences in membrane transport properties; and previously has been modelled by an equivalent electrical circuit and solved analytically. While effective, this approach did not fully account for all the anatomical and functional complexities of the lens. To encapsulate these complexities we have created a 3D finite element computer model of the lens.

Methods

Initially, we created an anatomically-correct representative mesh of the lens. We then implemented the Stokes and advective Nernst-Plank equations, in order to model the water and ion fluxes respectively. Next we complemented the model with experimentally-measured surface ionic concentrations as boundary conditions and solved it.

Results

Our model calculated the standing ionic concentrations and electrical potential gradients in the lens. Furthermore, it generated vector maps of intra- and extracellular space ion and water fluxes that are proposed to circulate throughout the lens. These fields have only been measured on the surface of the lens and our calculations are the first 3D representation of their direction and magnitude in the lens.

Conclusion

Values for steady state standing fields for concentration and electrical potential plus ionic and fluid fluxes calculated by our model exhibited broad agreement with observed experimental values. Our model of lens function represents a platform to integrate new experimental data as they emerge and assist us to understand how the integrated structure and function of the lens contributes to the maintenance of its transparency.     

Bestatin inhibits cell growth, cell division, and spore cell differentiation in Dictyostelium discoideum

Bestatin methyl ester (BME) is an inhibitor of Zn(2+)-binding aminopeptidases that inhibits cell proliferation and induces apoptosis in normal and cancer cells. We have used Dictyostelium as a model organism to study the effects of BME. Only two Zn(2+)-binding aminopeptidases have been identified in Dictyostelium to date, puromycin-sensitive aminopeptidase A and B (PsaA and PsaB). PSA from other organisms is known to regulate cell division and differentiation. Here we show that PsaA is differentially expressed throughout growth and development of Dictyostelium, and its expression is regulated by developmental morphogens. We present evidence that BME specifically interacts with PsaA and inhibits its aminopeptidase activity. Treatment of cells with BME inhibited the rate of cell growth and the frequency of cell division in growing cells and inhibited spore cell differentiation during late development. Overexpression of PsaA-GFP (where GFP is green fluorescent protein) also inhibited spore cell differentiation but did not affect growth. Using chimeras, we have identified that nuclear versus cytoplasmic localization of PsaA affects the choice between stalk or spore cell differentiation pathway. Cells that overexpressed PsaA-GFP (primarily nuclear) differentiated into stalk cells, while cells that overexpressed PsaAΔNLS2-GFP (cytoplasmic) differentiated into spores. In conclusion, we have identified that BME inhibits cell growth, division, and differentiation in Dictyostelium likely through inhibition of PsaA.     

Nucleocytoplasmic protein translocation during mitosis in the social amoebozoan Dictyostelium discoideum

Mitosis is a fundamental and essential life process. It underlies the duplication and survival of all cells and, as a result, all eukaryotic organisms. Since uncontrolled mitosis is a dreaded component of many cancers, a full understanding of the process is critical. Evolution has led to the existence of three types of mitosis: closed, open, and semi‐open. The significance of these different mitotic species, how they can lead to a full understanding of the critical events that underlie the asexual duplication of all cells, and how they may generate new insights into controlling unregulated cell division remains to be determined. The eukaryotic microbe Dictyostelium discoideum has proved to be a valuable biomedical model organism. While it appears to utilize closed mitosis, a review of the literature suggests that it possesses a form of mitosis that lies in the middle between truly open and fully closed mitosis—it utilizes a form of semi‐open mitosis. Here, the nucleocytoplasmic translocation patterns of the proteins that have been studied during mitosis in the social amoebozoan D. discoideum are detailed followed by a discussion of how some of them provide support for the hypothesis of semi‐open mitosis.