These studies demonstrated that CF-like airway surface dehydration causing mucociliary dysfunction and mucus obstruction [54,55] provides a robust stimulus for macrophage activation, even when Scnn1b-transgenic mice are kept in a germ-free environment [54, 56].
Further experiments implicated other H1N1 genes in the enhancement of mammal-to-mammal transmission, including nucleoprotein (NP), neuraminidase (NA), and matrix (M), as well as mutations in H5 HA that improve affinity for human-like airway receptors.
However, in contrast with the findings in βENaC-Tg/NE−/− mice, neither genetic deletion nor pharmacological inhibition of MMP12 reduced airway inflammation or goblet cell metaplasia in βENaC-Tg mice indicating that MMP12 is not essential in the in vivo pathogenesis of CF-like airway diseases [52].
Proximal-like airway tissues were often surrounded by a smooth muscle actin positive (SMA+) mesenchyme compartment.
Asthmatics have increased parasympathetic autonomic activity [ 21, 28, 29] and GER predisposes to asthma-like airway disease [ 4].
These data clearly demonstrate that PAI-1 targets trypsin-like airway proteases needed for extracellular virus maturation.
However, a study demonstrated that C5L2 is involved in the pathogenesis of asthma-like airway hyperresponsiveness and inflammation [ 7].
Importantly, we also show that these distal-like airway structures had abundant myofibroblasts, fibroblasts and smooth muscle cells, but not cartilage.
Human H441 Clara-like airway epithelial cells, cultured as monolayers at air interface, exhibit a number of similarities to primary cultured human airway epithelial cells and in vivo human airway (2, 6, 20).
In mice, the primary lung epithelial buds undergo reiterated elongation and division from E10.5, a process called branching morphogenesis, to form a tree-like airway structure with coordinated differentiation of epithelial and mesenchymal cells along proximal-distal airways.
Organoids persisted in culture for over 100 days and developed well-organized proximal-like airway epithelial structures that included many cell types found in the proximal lung epithelium, including basal and ciliated cells along with rare club cells.
