The lung is composed of a highly branched airway structure, which humidifies and warms the inhaled air before entering the alveolar compartment. In the alveoli, a thin layer of epithelium is in close proximity with the capillary endothelium, allowing for an efficient exchange of oxygen and carbon dioxide. During development proliferation and differentiation of progenitor cells generates the lung architecture, and in the adult lung a proper function of progenitor cells is needed to regenerate after injury. Malfunctioning of progenitors during development results in various congenital lung disorders, such as Congenital Diaphragmatic Hernia (CDH) and Congenital Pulmonary Adenomatoid Malformation (CPAM). In addition, many premature neonates experience continuous insults on the lung caused by artificial ventilation and supplemental oxygen, which requires a highly controlled mechanism of airway repair. Malfunctioning of airway progenitors during regeneration can result in reduction of respiratory function or (chronic) airway diseases. Pathways that are active during development are frequently re-activated upon damage. Understanding the basic mechanisms of lung development and the behavior of progenitor cell in the ontogeny and regeneration of the lung may help to better understand the underlying cause of lung diseases, especially those occurring in prenatal development or in the immediate postnatal period of life. This review provides an overview of lung development and the cell types involved in repair of lung damage with a focus on the airway.

Semaphorin3E belongs to the large family of semaphorin proteins. Semaphorin3E was initially identified as axon guidance cues in the neural system. It is universally expressed beyond the nervous system and contributes to regulating essential cell functions such as cell migration, proliferation, and adhesion. Binding of semaphorin3E to its receptor, plexinD1, triggers diverse signaling pathways involved in the pathogenesis of various diseases from cancer to autoimmune and allergic disorders. Here, we highlight the novel findings on the role of semaphorin3E in airway biology. In particular, we highlight our recent findings on the function and potential mechanisms by which semaphorin3E and its receptor, plexinD1, impact airway inflammation, airway hyperresponsiveness, and remodeling in the context of asthma.

Anatomic measurements of the right (RMB) and left mainstem bronchi (LMB) in infants and children have been accomplished using various modalities. The objective of the present review was to determine whether enough data were available to provide standardized lower airway dimensions in the pediatric population. For the present study, 12 studies with data of the lower pediatric airway dimensions of 1,611 children published from 1923-2020 were reviewed and analyzed. The eligible criteria included studies measuring lower airway dimensions in the pediatric population. Various techniques were used for airway measurement, with computed tomography studies being most abundant. There was a progressive increase in the size of RMB and LMB with age, with a close approximation of the LMB-to-RMB ratio across all studies. In children younger than 1 year old, the RMB and LMB diameters were between 4 and 5 mm and 3 and 5 mm, respectively. Overall, there was significant variation in the methods and modality used to obtain measurements, and therefore it was difficult to establish standardized lower airway dimensions in the pediatric population. Additional homogeneous data with standardized measurement techniques and modalities across different pediatric age groups are needed to define these dimensions further. Such data may be helpful in designing airway equipment, lung isolation devices, and airway stents.

Semaphorins are a large family of proteins originally identified as axon guidance cues that play a crucial role in neural development. They are also ubiquitously expressed beyond the nervous system and contribute to regulation of essential cell functions, such as cell migration, proliferation, and adhesion. Binding of semaphorins to their receptors, including plexins and neuropilins, triggers diverse signaling pathways, which are involved in the pathogenesis of various diseases, from cancer to autoimmune and allergic disorders. Despite emerging evidence suggestive of nonredundant roles of semaphorins in cellular and molecular mechanisms of the airway biology, their precise expression and function have not been fully addressed. Here, we first provide an overview about the semaphorin family, their receptors, signaling pathways, and their cellular functions. Then, we highlight the novel findings on the role of semaphorins in airway biology under developmental, homeostatic, and pathological conditions. In particular, we discuss the dual roles of semaphorins in respiratory disorders where they can up- or downregulate processes underlying the pathophysiology of the airway diseases. Next, our recent findings on the expression and function of semaphorin 3E in allergic asthma are further emphasized, and its potential mechanism of action in allergic airway inflammation and remodeling is discussed. Finally, we raise some unanswered questions aiming to develop future research directions.

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BACKGROUND: People with cystic fibrosis (CF) sinus disease have developmental sinus abnormalities with airway bacterial infection, inflammation, impaired mucociliary clearance and thick obstructive mucus. The pathophysiology of airway disease in CF is not completely understood, and current treatments in CF sinus disease ameliorate symptoms but do not provide a cure.
METHODS: This manuscript reviews the history of CF, its manifestations in sinus disease, and the potential impact and relationship of CF on the upper and lower airway.
RESULTS: There is increasing evidence that CF sinus disease may affect CF lung disease, the most common cause of mortality in CF. We have been limited in treating the symptoms of advanced CF sinus disease with our current therapies.
CONCLUSIONS: Recent discoveries in the pathophysiology of CF using the CF porcine animal model and exciting treatments that address the primary gene defect that may translate into improved outcomes in CF and non-CF sinusitis in humans.

Mesenchymal cells (fibroblasts) of the airway wall respond to cholinergic stimulation by releasing pro-inflammatory and chemotactic cytokines and may thus contribute to chronic inflammation of the lung. Here, we studied the anti-inflammatory potential of olodaterol, a long acting β2-adrenergic receptor agonist, and tiotropium, a long-acting muscarinic receptor antagonist, and whether they interact at the level of the cyclic AMP dependent signaling pathway. Pulmonary fibroblasts of asthmatic (n = 9) and non-asthmatic (n = 8) subjects were stimulated with the muscarinic receptor agonist carbachol and interleukin-1β (IL-1 beta) in presence or absence of tiotropium or olodaterol alone, or their combination. We also measured cAMP levels and phosphorylation of the cAMP response element binding protein (CREB). As single components, carbachol, olodaterol and tiotropium did not affect IL-6 and IL-8 release. Carbachol concentration-dependently enhanced the production of IL-1β-induced IL-6 and IL-8, which was blocked by the simultaneous addition of tiotropium. The combination of olodaterol plus tiotropium further reduced IL-6 and IL-8 release. Olodaterol induced cAMP and the phosphorylation of CREB, an effect counteracted by carbachol, but rescued by tiotropium. We conclude that olodaterol plus tiotropium cooperate to decrease the inflammatory response in pulmonary fibroblasts in vitro.