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Ochs M.,Hannover Medical School | Ochs M.,Biomedical Research in Endstage and Obstructive Lung Disease Hanover | Reinhardt J.M.,University of Iowa | Hoffman E.A.,University of Iowa | And 2 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: Air trappingandairflow obstruction are being increasingly identifiedin infants with cystic fibrosis. Thesefindings arecommonly attributed to airway infection, inflammation, and mucus buildup. Objectives: To learn if air trappingandairflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis. Methods: On the day they are born, piglets with cystic fibrosis lack airway infection and inflammation. Therefore, we used newborn wild-type piglets and piglets with cystic fibrosis to assess air trapping, airway size, and lung volume with inspiratory and expiratory X-ray computed tomography scans. Micro-computed tomography scanning was used to assess more distal airway sizes. Airway resistance was determined with a mechanical ventilator. Mean linear intercept and alveolar surface area were determined using stereologic methods. Measurements and Main Results: On the day they were born, piglets with cystic fibrosis exhibited air trapping more frequently than wild-type piglets (75% vs. 12.5%, respectively). Moreover, newborn piglets with cystic fibrosis had increased airway resistance that was accompanied by luminal size reduction in the trachea, mainstem bronchi, and proximal airways. In contrast, mean linear intercept length, alveolar surface area, and lung volume were similar between both genotypes. Conclusions: The presence of air trapping, airflow obstruction, and airway size reduction in newborn piglets with cystic fibrosis before the onset of airway infection, inflammation, and mucus accumulation indicates that cystic fibrosis impacts airway development. Our findings suggest that early airflow obstruction and air trapping in infants with cystic fibrosis might, in part, be caused by congenital airway abnormalities. Copyright © 2013 by the American Thoracic Society.


McDonough J.E.,Center for Heart Lung Innovation | Knudsen L.,Hannover Medical School | Knudsen L.,Biomedical Research in Endstage and Obstructive Lung Disease Hanover | Wright A.C.,University of Pennsylvania | And 4 more authors.
Journal of Applied Physiology | Year: 2015

The gravity-dependent pleural pressure gradient within the thorax produces regional differences in lung inflation that have a profound effect on the distribution of ventilation within the lung. This study examines the hypothesis that gravitationally induced differences in stress within the thorax also influence alveolar density in terms of the number of alveoli contained per unit volume of lung. To test this hypothesis, we measured the number of alveoli within known volumes of lung located at regular intervals between the apex and base of four normal adult human lungs that were rapidly frozen at a constant transpulmonary pressure, and used microcomputed tomographic imaging to measure alveolar density (number alveoli/mm3) at regular intervals between the lung apex and base. These results show that at total lung capacity, alveolar density in the lung apex is 31.6 ± 3.4 alveoli/mm3, with 15 ± 6% of parenchymal tissue consisting of alveolar duct. The base of the lung had an alveolar density of 21.2 ± 1.6 alveoli/mm3 and alveolar duct volume fraction of 29 ± 6%. The difference in alveolar density can be negated by factoring in the effects of alveolar compression due to the pleural pressure gradient at the base of the lung in vivo and at functional residual capacity. Copyright © 2015 the American Physiological Society.


Fritzsching B.,University of Heidelberg | Fritzsching B.,Translational Lung Research Center Heidelberg | Zhou-Suckow Z.,University of Heidelberg | Zhou-Suckow Z.,Translational Lung Research Center Heidelberg | And 27 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways frompatients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease. Objectives: To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease. Methods: Weused genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis. Measurements and Main Results: Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, butabrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated withmucus obstruction in patients with CF and chronic obstructive pulmonary disease. Conclusions: Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases. Copyright © 2015 by the American Thoracic Society.


Willfuhr A.,Hannover Medical School | Brandenberger C.,Hannover Medical School | Piatkowski T.,Hannover Medical School | Piatkowski T.,Max Planck Institute for Heart and Lung Research | And 6 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2015

The lung parenchyma provides a maximal surface area of blood-containing capillaries that are in close contact with a large surface areaof the air-containing alveoli. Volume and surface area of capillaries are the classic stereological parameters to characterize the alveolar capillary network (ACN) and have provided essential structure-function information of the lung. When loss (rarefaction) or gain (angiogenesis) of capillaries occurs, these parameters may not be sufficient to provide mechanistic insight. Therefore, it would be desirable to estimate the number of capillaries, as it contains more distinct and mechanistically oriented information. Here, we present a new stereological method to estimate the number of capillary loops in the ACN. One advantage of this method is that it is independent of the shape, size, or distribution of the capillaries. We used consecutive, 1 _mthick sections from epoxy resin-embedded material as a physical disector. The Euler-Poincaré characteristic of capillary networks can be estimated by counting the easily recognizable topolog ical constellations of “islands,” “bridges,” and “holes.” The total number of capillary loops in the ACN can then be calculated from the Euler- Poincaré characteristic. With the use of the established estimator of alveolar number, it is possible to obtain the mean number of capillary loops per alveolus. In conclusion, estimation of alveolar capillaries by design-based stereology is an efficient and unbiased method to characterize the ACN and may be particularly useful for studies on emphysema, pulmonary hypertension, or lung development. © 2015 the American Physiological Society.


Vogel-Claussen J.,Hannover Medical School | Vogel-Claussen J.,Biomedical Research in Endstage and Obstructive Lung Disease Hanover | Renne J.,Hannover Medical School | Renne J.,Biomedical Research in Endstage and Obstructive Lung Disease Hanover | And 20 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: There is a need to develop novel noninvasive imaging biomarkers that help to evaluate antiinflammatory asthma treatments. Objectives: To investigate whether the extent of the segmental lung edema measured noninvasively using turbo-inversion recoverymagnitude magnetic resonance imaging (TIRM MRI) corresponds to the severity of the regional allergic reaction determined by the percentage of eosinophils in bronchoalveolar lavage fluid (BAL) 24 hours after segmental allergen challenge in patients with asthma compared with normal control subjects. Methods: Eleven volunteers with allergic asthma and five healthy volunteers underwent segmental challenges with different allergen doses by two bronchoscopies 24 hours apart. They had lung MRI at baseline and 6 and 24 hours after segmental challenge. MRI TIRM scores were correlated with the eosinophilic response at 24 hours. Measurements and Main Results: In patients with asthma, there were significant differences of eosinophil percentages in BAL at 24 hours from segments given standard-dose, low-dose, or no allergen (saline) (P,0.001). Correspondingly significant differences between the TIRM score in allergen standard-dose, low-dose, and salinetreated segments were observed at 24 hours post-challenge (P > 0.001). With increasing TIRM score at 24 hours the percent eosinophils per segment 24 hours post-challenge also increased accordingly (P > 0.001). There was interobserver agreement for TIRM score grading (kappa = 0.72 for 24-h time point). Conclusions: The MRI-based noninvasive TIRM score is a promising biomarker for the noninvasive detection of the inflammatory response after segmental allergen challenge in patients with asthma and may serve to monitor the therapeutic effectiveness of novel antiinflammatory drugs in future human trials.Copyright © 2014 by the American Thoracic Society.

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