U-M Pulmonary & Critical Care scientists have top papers in J. Immunology

The Pulmonary and Critical Care Medicine Division of the University of Michigan is featured prominently in the July 1st edition of the Journal of Immunology.

The July 1 edition of the Journal of Immunology contains three articles from the U-M Division of Pulmonary and Critical Care Medicine. These three articles not only highlight the diversity of the Division’s research, but are significant because two were highlighted “In this Issue” by their peer-reviewers as work in the top 10% of all studies submitted to the Journal of Immunology.

Equally excitingly, these articles principally represent the efforts of three of our outstanding young women scientists (Megan Ballinger, Ph.D., Melissa Kovach, M.D. and Alexandra McCubbrey, Ph.D. candidate in Immunology), illustrating the leading role of the University of Michigan to reverse gender inequality in the life sciences. A brief synopsis of each article is presented below

TLR Signaling Prevents Hyperoxia-Induced Lung Injury by Protecting the Alveolar Epithelium from Oxidant-Mediated Death
Megan N. Ballinger, Michael W. Newstead, Xianying Zeng, Urvashi Bhan, Jeffrey C. Horowitz, Bethany B. Moore, David J. Pinsky, Richard A. Flavell, and Theodore J. Standiford
J Immunol 2012 189:356-364; recognized “In this Issue” for work in Inflammation

Although it may seem counter-intuitive, in patients with respiratory failure, the process of mechanical ventilation can cause further lung damage due to the harmful effects of too much oxygen (or hyperoxia). The ability of the lung to protect itself against hyperoxic lung injury involves the upregulation of anti-oxidant molecules and the release of anti-oxidants can be triggered through activation of a class of molecules called toll-like receptors (TLRs), but exactly how this process is regulated in the lung is unknown.

Ballinger and her colleagues hypothesized that a molecule which has previously been described as a negative regulator of TLR signaling in myeloid cells might also play a role in limiting TLR activation in structural cells within the lung. She demonstrated that the negative regulator called IRAK-M is elevated in lung epithelial cells in response to hyperoxic injury. Using genetically modified mice which do not express IRAK-M, she demonstrated that absence of IRAK-M in structural cells, but not myeloid (or inflammatory) cells allowed mice to survive hyperoxic injury much better and the deletion of IRAK-M in the structural cells prevented lung epithelial cell death and limited the flooding of the lung with fluids preventing suffocation. These results are significant for several reasons. First, they provide new information about the function of IRAK-M, a newly discovered molecule in epithelial cells of the lung during lung injury. More importantly however, these results suggest that therapeutic strategies which could limit expression of IRAK-M in epithelial cells should improve outcomes for patients with respiratory failure who require mechanical ventilation. This is highly significant given that up to 40% of patients requiring mechanical ventilation due not survive due to the complications of hyperoxia.

Cathelicidin-Related Antimicrobial Peptide Is Required for Effective Lung Mucosal Immunity in Gram-Negative Bacterial Pneumonia
Melissa A. Kovach, Megan N. Ballinger, Michael W. Newstead, Xianying Zeng, Urvashi Bhan, Fu-shin Yu, Bethany B. Moore, Richard L. Gallo, and Theodore J. Standiford
J Immunol 2012 189:304-311; published in the section on Host Defense.

One of the most serious complications which can arise in hospitalized patients is the development of pneumonia commonly caused by Gram-negative bacterial species. In fact, the bacteria Klebsiella pneumoniae is now responsible for approximately 10% of all hospital-acquired infections and the bacteria Pseudomonas aeruginosa accounts for up to 40% of these infections which can result in significant mortality. With the rise of antibiotic resistant strains of bacteria, there is a need to better understand the natural defense mechanisms that operate in the lung to help clear such pathogens. One class of molecules that are important for anti-microbial host defense against infections are antimicrobial peptides, which include cathelicidins. Cathelicidins can be secreted and activated by various cell types and they interfere with bacterial cell growth via electrostatic interactions with the bacterial cell wall. In this issue, Kovach and her colleagues describe the importance of a particular cathelicidin protein known as cathelicidin-related antimicrobial peptide or CRAMP to limit infection by both Klebsiella pneumoniae and Pseudomonas aeruginosa. She demonstrated the importance of inflammatory cell release of CRAMP in the setting of bacterial infection. When CRAMP was present, total numbers of Klebsiella pneumoniae bacteria in the lung, as well as bacterialdissemination to other organs, was reduced. She also showed the ability of CRAMP to improve the clearance of infection with Pseudomonas aeruginosa. Another important aspect of this work was to identify that CRAMP plays an important role in recruiting inflammatory cells called neutrophils to the lung early in the course of infection to help clear bacteria. These data are significant because they demonstrate the ability of an endogenous protein made by inflammatory cells and lung structural cells to limit the replication of pathogenic Gram negative bacteria. This suggests that therapeutic strategies to enhance production of CRAMP may allow infected patients to clear these lung infections, even if they are resistant to current antibiotics. Such an advance would tremendously improve mortality rates in patients who acquire an infection in the hospital.

Glucocorticoids Relieve Collectin-Driven Suppression of Apoptotic Cell Uptake in Murine Alveolar Macrophages through Downregulation of SIRPa
Alexandra L. McCubbrey, Joanne Sonstein, Theresa M. Ames, Christine M. Freeman, and Jeffrey L. Curtis; J Immunol 2012 189:112-119; recognized “In this Issue” for work in Cellular Immunology and Immune Regulation

Inhaled steroids (“glucocorticoids”) are widely prescribed to treat inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). But is not entirely clear how these drugs work to improve symptoms and lung function. In inflammatory lung disease, many white blood cells and structural cells die in the lungs. It is crucial that these dying (“apoptotic”) cells be cleared efficiently to prevent more lung damage; in fact, the clearance process itself reduces inflammation. One key resident lung cell type, alveolar macrophages, typically clear apoptotic cells inefficiently due to inhibition by lung surfactant proteins. These surfactant proteins (SpA and SpD), also called “collectins”, bind an inhibitory receptor on alveolar macrophages called signal regulatory protein alpha (SIRPa), blocking uptake of dying cells. Using a mouse model, McCubbrey and her colleagues tested the ability of a commonly prescribed inhaled corticosteroid (fluticasone) to change apoptotic cell uptake by alveolar macrophages. She found that fluticasone caused two changes in the alveolar macrophages: rapid (hours) increased binding and uptake of apoptotic cells that did not require new protein synthesis and depended on reduced expression of SIRPa, and a slower program of gene upregulation that continued to increase uptake over days. Only the second effect was seen in macrophages from another body surface, the peritoneum, even though glucocorticoid treatment also decreased SIRPa expression on these macrophages. However, peritoneal macrophages are not normally exposed to collectins. Once peritoneal macrophages were exposed to SpD, uptake of apoptotic cells was decreased and this change could be rapidly reversed by fluticasone, confrming that the fluticasone-induced rapid changes in apoptotic cell uptake were through blocking the unique collectin-SIRPa pathway of the lung. These results provide key mechanistic insight into one way that inhaled corticosteroids help resolve inflammation in asthma and COPD.

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