Mice lacking surfactant protein (SP)-A (SP-A−/−) or SP-D (SP-D−/−) and wild-type mice were infected with group B streptococcus or Haemophilus influenzae by intratracheal instillation. Although decreased killing of group B streptococcus and H. influenzae was observed in SP-A−/− mice but not in SP-D−/− mice, deficiency of either SP-A or SP-D was associated with increased inflammation and inflammatory cell recruitment in the lung after infection. Deficient uptake of bacteria by alveolar macrophages was observed in both SP-A- and SP-D-deficient mice. Isolated alveolar macrophages from SP-A−/− mice generated significantly less, whereas those from SP-D−/− mice generated significantly greater superoxide and hydrogen peroxide compared with wild-type alveolar macrophages. In SP-D−/− mice, bacterial killing was associated with increased lung inflammation, increased oxidant production, and decreased macrophage phagocytosis. In contrast, in the absence of SP-A, bacterial killing was decreased and associated with increased lung inflammation, decreased oxidant production, and decreased macrophage phagocytosis. Increased oxidant production likely contributes to effective bacterial killing in the lungs of SP-D−/− mice. The collectins, SP-A and SP-D, play distinct roles during bacterial infection of the lung.

Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (Vhl R/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating Vhl R/R mice as a model for Chuvash disease. Lungs from Vhl R/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2α activity was increased in lungs from Vhl R/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the Vhl R/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in Vhl R/R lungs, suggesting a selective role for HIF-2α in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2α and suggest potential treatments for Chuvash patients.

No abstract

To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc−/−) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc−/−ice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc−/− mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc−/− mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc−/− mice relative to Sftpc+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc−/− mice following infection. Phagocytic activity of alveolar macrophages from Sftpc−/− mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc−/− mice. Alveolar macrophages from Sftpc−/− mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses.

MR imaging based treatment planning for radiotherapy of prostate cancer is limited due to MR imaging system related geometrical distortions, especially for patients with large body sizes. On our 0.23 T open scanner equipped with the gradient distortion correction (GDC) software, the residual image distortions after the GDC were <5 mm within the central 36 cm x 36 cm area for a standard 48 cm field of view (FOV). In order to use MR imaging alone for treatment planning the effect of residual MR distortions on external patient contour determination, especially for the peripheral regions outside the 36 cm x 36 cm area, must be investigated and corrected. In this work, we performed phantom measurements to quantify MR system related residual geometric distortions after the GDC and the effective FOV. Our results show that for patients with larger lateral dimensions (>36 cm), the differences in patient external contours between distortion-free CT images and GDC-corrected MR images were 1-2 cm because of the combination of greater gradient distortion and loss of field homogeneity away from the isocentre and the uncertainties in patient setup during CT and MRI scans. The measured distortion maps were used to perform point-by-point corrections for patients with large dimensions inside the effective FOV. Using the point-by-point method, the geometrical distortion after the GDC were reduced to <3 mm for external contour determination and the effective FOV was expanded from 36 cm to 42 cm.