Exploiting mechanical stimuli to rescue growth of the hypoplastic lung

Abstract

Impaired lung development afflicts a range of newborns cared for by paediatric surgeons. As a result the speciality has led in the development of surgical models that illustrate the biomechanical regulation of lung growth. Using transgenic mutants, biologists have similarly discovered much about the biochemical regulation of prenatal lung growth. Airway smooth muscle (ASM) and its prenatal contractility airway peristalsis (AP) represent a novel link between these areas: ASM progenitors produce an essential biochemical factor for lung morphogenesis, whilst calcium-driven biomechanical ASM activity appears to regulate the same. In this invited paper, I take the opportunity both to review our recent findings on lung growth and prenatal ASM, and also to discuss mechanisms by which ASM contractility can regulate growth. Finally, I will introduce some novel ideas for exploration: ASM contractility could help to schedule parturition (pulmonary parturition clock) and could even be a generic model for smooth muscle regulation of morphogenesis in similar organs.

Airway smooth muscle: an architect of the lung?

“…In summary, despite considerable investigation of postnatal ASM, there is still no agreement as to its function. However, of the physiological functions that have been suggested in humans, potential roles in lung development are now being elucidated 11. Dismissing ASM as an evolutionary vestige may yet be premature.…”

Stem Cells, Tissue Engineering and Regenerative Medicine

“…These areas of enquiry have grown out of a specific and highly refractory clinical problem, hypoplastic lung development, which will therefore be described briefly below. [5][6][7][8] Like many clinical concepts, lung hypoplasia is a messy one, with fuzzy definitions and frustratingly limited therapeutic options. As the name suggests, the set is defined by lungs that underperform at birth due to inadequately developed surface area for gas exchange.…”

“…It has therefore been argued that this is helpful in distributing hydraulic pressure throughout the developing structure, and indeed maintaining that pressure locally. 7,43 Airway peristalsis begins shortly after the onset of lung development (equivalent to a few weeks of human gestation) and continues toward term. So despite radical changes that occur in lung epithelia over this time, the contractility persists and indeed increases in frequency as birth approaches.…”

“…14,15 Similarly, during normal development, the lung is variously shaken by mechanical activity, from airway peristalsis, lung liquid fluctuations and fetal breathing movements. 7,10 Yet, the importance of these stimuli for lung progenitor cells is really only just being glimpsed.…”

Abnormal Sonic hedgehog signaling in the lung of rats with esophageal atresia induced by adriamycin

“…Furthermore, "erratic" behavior of the signaling pathway in these lungs suggests a disturbed pathway in some way different from the adria EA-TEF lungs eventually responsible for the different embryo phenotype induced by adriamycin administration (with or without EA-TEF). In addition, the putative effect of the tracheoesophageal fistula in lung organogenesis and growth must be considered, because Shh expression is also stimulated by physical pressures (26)(27)(28), and the disturbed swallowing plus the gastrointestinal obstruction seen in EA may perturb the lung dynamics exceptionally important for lung development. In summary, and despite the absence of a semiquantitative protein assessment not allowing a discussion based on functional protein contents, immunofluorescence results seemed to be consistent with the real-time RT-PCR results.…”