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Rochester, MN, United States

Vadasz I.,Justus Liebig University | Hubmayr R.D.,Thoracic Diseases Research Unit | Nin N.,CIBER ISCIII | Sporn P.H.S.,Northwestern University | And 2 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2012

Patients with severe acute and chronic lung diseases develop derangements in gas exchange thatmay result in increased levels of CO 2 (hypercapnia), the effects of which on human health are incompletely understood. It has been proposed that hypercapniamay have beneficial effects in patients with acute lung injury, and the concepts of "permissive" and even "therapeutic" hypercapnia have emerged. However, recent work suggests that CO 2 can act as a signaling molecule via pH- independentmechanisms, resulting in deleterious effects in the lung. Here we review recent research on how elevated CO 2 is sensed by cells in the lung and the potential harmful effects of hypercapnia on epithelial and endothelial barrier, lung edema clearance, innate immunity, and host defense. In viewof these findings,we raise concerns about the potentially deleterious effects hypercapnia may have in patients with acute and chronic lung diseases. Source

Limper A.H.,Thoracic Diseases Research Unit | Limper A.H.,Foundation Medicine
Proceedings of the American Thoracic Society | Year: 2010

Fungal lung infections are being diagnosed with increasing frequency. This is related to the increased numbers of immune-compromised and other susceptible patient groups. This article will focus on the evolving epidemiology of fungal lung infections and clinical manifestations that should prompt the clinician to consider the possibility of fungal lung infection. In addition, current approaches for the diagnosis of these infection are also reviewed. Heightened awareness of fungal lung infection, and appropriate use of the available diagnostic modalities, will permit appropriate treatment of these important clinical infections in immune-compromised individuals. Source

Suki B.,Boston University | Hubmayr R.,Thoracic Diseases Research Unit
Current Opinion in Critical Care | Year: 2014

PURPOSE OF REVIEW: The adult respiratory distress syndrome (ARDS) is a common cause of respiratory failure with substantial impact on public health. Patients with ARDS generally require mechanical ventilation, which risks further lung damage. Recent improvements in ARDS outcomes have been attributed to reductions in deforming stress associated with lung protective mechanical ventilation modes and settings. The following review details the mechanics of the lung parenchyma at different spatial scales and the response of its resident cells to deforming stress in order to provide the biologic underpinnings of lung protective care. RECENT FINDINGS: Although lung injury is typically viewed through the lens of altered barrier properties and mechanical ventilation-Associated immune responses, in this review, we call attention to the importance of heterogeneity and the physical failure of the load bearing cell and tissue elements in the pathogenesis of ARDS. Specifically, we introduce a simple elastic network model to better understand the deformations of lung regions, intra-Acinar alveoli and cells within a single alveolus, and consider the role of regional distension and interfacial stress-related injury for various ventilation modes. SUMMARY: Heterogeneity of stiffness and intercellular and intracellular stress failure are fundamental components of ARDS and their development also depends on the ventilation mode. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Kottom T.J.,Thoracic Diseases Research Unit | Han J.,Mayo Medical School | Zhang Z.,Mayo Medical School | Limper A.H.,Thoracic Diseases Research Unit
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

Species in the genus Pneumocystis can cause severe pneumonia in immune-compromised hosts. The identification of specific targets present in Pneumocystis species, but lacking in mammalian hosts, is paramount to developing new means to treat this infection. One such potential protein is Rtt109, which is a type of histone acetyltransferase (HAT) required for DNA replication in fungi, but not found in mammals. Sequence orthologues of Rtt109 are present in other fungi, but are absent in mammals, making it a potential panspecific target against medically relevant fungi. Accordingly, we sought to identify the presence of an Rtt109 in P. carinii. A Pneumocystis carinii (Pc) Rtt109 165-bp partial sequence was initially identified from the incomplete P. carinii genome database. Subsequently, a full-length, 1,128-bp cDNA with homology to Saccharomyces cerevisiae Rtt109 (39% Basic Local Alignment Search Tool (BLASTP)) was cloned and characterized. Sequence analysis of PcRtt109 indicated that the P. carinii molecule contains the putative catalytic aspartate present in yeast. We further demonstrated that the PcRtt109 expressed in rtt109Δ S. cerevisiae cells restored H3-K56 acetylation and the sensitivity toward DNA-damaging agents of rtt109Δ mutant cells. Purified PcRtt109 had the ability to acetylate lysine-56 of histone H3, similar to the ability of Schizosaccharomyces pombe Rtt109 protein. The site-directed mutagenesis of PcRtt109 D84A, a potential regulatory site in the Rtt109 HAT family, abolished H3 acetylation, whereas a DD218/219AA mutation that compromised the activity of ScRtt109 had little effect, demonstrating similarities and differences in Pneumocystis PcRtt109 compared with yeast Saccharomyces cerevisiae Rtt109. These results indicate that P. carinii contains an Rtt109 HAT molecule, and represent the complete identification and characterization of a HAT molecule from this important opportunistic fungal pathogen. Source

Kottom T.J.,Thoracic Diseases Research Unit | Limper A.H.,Thoracic Diseases Research Unit
Journal of Biological Chemistry | Year: 2013

Background: Ace2 transcription factors regulate fungal cell wall remodeling. Results: Pneumocystis carinii Ace2 (PcAce2) is activated by lung matrix proteins and participates in fungal virulence. Conclusion: PcAce2 represents a key component of life cycle regulation that is induced by Pneumocystis contact with host substrates. Significance: This is the first example demonstrating a contact-induced activation of the Ace2 transcription factor. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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