Project description:ALK3 (BMPR1a) is a type-1-receptor of the TGF-β-receptor superfamily, which translates mostly bone morphogenetic proteins, but also TGF-β1. Previously, we could show that specific deletion of ALK3 in APCs leads to increased inflammation in the skin. Whether this effect is specific to the skin or found in other tissues as well has been unknown so far.Here, we used ALK3ΔCD11c-mice as well as pharmacological blockade of ALK3-signaling with DMH-1 to investigate the role of ALK3 in Bleomycin- and LPS-induced lung inflammations. We analysed lung inflammation via histology and studied the immune reaction via flow cytometry and single-cell-RNA-sequencing. Fitting to our results from the skin, we found that deletion or blockade of ALK3 aggravates long-lasting lung inflammations by reducing the number of TREG. Thus, ALK3 in APCs is important for dampening chronic lung inflammations. Surprisingly, we observed the opposite effect in acute inflammations: here, blockade of ALK3 ameliorated the inflammation. We found that ALK3 acts on APCs, reducing their state of activation and changing the secretion of chemokines. This in turn reduces activity of neutrophils, leading to reduced lung inflammation.Thus, ALK3 has a dual role in lung inflammations. It contributes to initiation of acute inflammation, but dampens longer-lasting inflammations.
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Transplanted DASC cells incorporated into damaged host lung were laser capture microdissected and analyzed. Duplicate mice were included. We used the Affymetrix Mouse Exon 1.0 ST platform
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. DASC stem cells were ablated by Dtox treatment in Krt6:DTR mouse model. Control and stem cell ablated lungs were analyzed. We used the Affymetrix Mouse Exon 1.0 ST platform
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Stem cells before and after in vitro differentiation were subjected to whole genome microarray analysis. Duplicates were included for each sample. We used the Affymetrix Mouse Exon 1.0 ST platform
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases. Tracheal epithelium and alveoli of healthy mice were laser capture microdissected for microarray analysis. Damaged lung interstitium (CD45+ region) of influenza infected (75pfu H1N1, 15dpi) mice were also dissected. Duplicates were included for each sample. We used the Affymetrix Mouse Exon 1.0 ST platform
Project description:Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics, has potent anti-inflammatory, anti-fibrotic and antioxidant properties. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed may modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury. We evaluated gene expression in lungs of flaxseed-fed (10% FS) mice under unchallenged, control conditions and 48hrs post-radiation treatment (13.5 Gy). Gene expression levels in lung tissues were analyzed using three arrays for each sample, whereby a total of 28,800 genes were evaluated. C57BL/6 black mice were fed a 10% flaxseed diet for 21 days and/or given 13.5Gy thoracic radiation and sacrificed 48hrs post radiation.
Project description:Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics, has potent anti-inflammatory, anti-fibrotic and antioxidant properties. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed may modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury. We evaluated gene expression in lungs of flaxseed-fed (10% FS) mice under unchallenged, control conditions and 48hrs post-radiation treatment (13.5 Gy). Gene expression levels in lung tissues were analyzed using three arrays for each sample, whereby a total of 28,800 genes were evaluated. C57BL/6 black mice were fed a 10% flaxseed diet for 21 days and/or given 13.5Gy thoracic radiation and sacrificed 48hrs post radiation.
Project description:Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics, has potent anti-inflammatory, anti-fibrotic and antioxidant properties. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed may modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury. We evaluated gene expression in lungs of flaxseed-fed (10% FS) mice under unchallenged, control conditions and 48hrs post-radiation treatment (13.5 Gy). Gene expression levels in lung tissues were analyzed using three arrays for each sample, whereby a total of 28,800 genes were evaluated. C57BL/6 black mice were fed a 10% flaxseed diet for 21 days and/or given 13.5Gy thoracic radiation and sacrificed 48hrs post radiation.
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases.
Project description:The possibility of lung regeneration has been long discounted due to the irreversible nature of chronic lung diseases. However, patients who sustain massive loss of lung tissue during acute infections often recover full pulmonary function. Correspondingly, we previously demonstrated lung regeneration in mice following H1N1 influenza virus infection and implicated p63+Krt5+ distal airway stem cells, or DASCp63/Krt5, in this process. We show here that rare, preexisting DASCp63/K5 undergo a proliferative expansion in response to influenza and lineage-trace to nascent alveoli assembled at sites of interstitial inflammation. We also show that the ablation of DASCp63/Krt5 in vivo prevents the regeneration of lung tissue following influenza leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that exogenously cloned and propagated DASCp63/Krt5 readily contribute to lung regeneration following transplantation. The transplanted DASC ameliorated influenza-induced lung injury. These data suggest that DASCp63/K5 are required for lung regeneration and may have therapeutic utility in acute and chronic lung diseases.