Mechanisms and Limits of Induced Postnatal Lung Growth

Abstract

Abnormal DevelopmentClinical syndromes. Syndromes that alter expression of growth factors, cytokines, transcription factors, or extracellular matrix (ECM) proteins provide models to explore mechanisms that control alveolar development. Signals that regulate the saccularto-alveolar morphologic transition are poorly understood, but disrupting lung septation during this transition impairs alveolar formation, resulting in a loss of alveolar surface area (20, 21). There are several syndromes of abnormal lung alveolarization in humans. Trisomy 21 (Down syndrome) is associated with reduced lung volumes, alveolar surface area, fewer alveoli, defective elastin deposition, and vascular abnormalities (22, 23). Leprechaunism, caused by a defect of the insulin/insulin-like growth factor-I receptor, is associated with reduced lung surface areas as well as fewer and larger alveoli (24). Oligohydramnios (25), congenital diaphragmatic hernia (CDH) (26), and intrathoracic mass lesions are all associated with pulmonary hypoplasia caused by the lack of interplay between thoracic expansion and stretch imposed on the lung. Lung hypoplasia in CDH is not just a consequence of mechanical lung compression caused by a hole in the diaphragm but also involves primary developmental defects (27). Prenatal tracheal occlusion markedly increases lung size in some fetuses with severe CDH; however, survival remains poor because of respiratory insufficiency and prematurity (28). After CDH repair, significant postnatal alveolar growth and vascular remodeling are seen (26); long-term survivors show lower lung volumes but normal airway function and exercise tolerance (29), suggesting the occurrence of "catch-up" lung growth once the underlying abnormalities are corrected.By far the most common cause of abnormal postnatal human lung development is bronchopulmonary dysplasia (BPD). Classically, BPD occurs in the preterm infant lung exposed to hyperoxia and mechanical ventilation (30-32), resulting in extensive alveolar fibroproliferation, bronchovascular smooth muscle hyperplasia, and inhibition of distal lung formation leading to longterm pulmonary dysfunction persisting into adolescence and adulthood. The advent of antenatal steroids, postnatal surfactant replacement, and improved intensive care has ushered in the "new BPD," which lacks the severe bronchovascular lesions and interstitial fibrosis but is characterized by abnormal lung development with simplified acinar structure, poorly formed secondary crests, dysmorphic alveolar capillaries, and blunted expression of angiogenic growth factors and their receptors (33-36). There is little information on the pathology of "new BPD" in infants who survive; it remains to be seen whether long-term "catch-up" lung growth occurs in these survivors.

Repair and Regeneration of the Respiratory System: Complexity, Plasticity, and Mechanisms of Lung Stem Cell Function

“…These fibers form an integrated network throughout the alveolar region, providing a flexible and elastic scaffold that is critical for maintaining lung function and for keeping the small terminal airways and alveolar ducts open (Weibel, 2013). Mechanical forces and physical stress are emerging as key regulators of alveolar development, maintenance, repair and regrowth (reviewed in (Hsia et al, 2004; Wirtz and Dobbs, 2000). …”

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

“…Similarly to humans, lambs exhibit several key features of RSV-vaccine enhanced disease; 14 anatomically, the respiratory tract of sheep and humans share many structural features, such as the size of the nasal cavity and airways, 15 as well as lung development where alveolarization starts pre-term 16 . When experimentally infected with either bovine (bRSV) or human (hRSV) strains of RSV, neonatal lambs develop mild clinical symptoms including fever, tachypnea or increased expiratory effort (wheeze) and malaise, as well as mild to moderate gross and histologic lesions 17 …”

Mechanostructural adaptations preceding postpneumonectomy lung growth

“…The growth of the remaining lung reflects not simply an increase in alveolar size, but an increase in the number of alveoli [1]. The consequences of this process have been well-documented [2]; but the mechanisms controlling compensatory lung growth are unknown.…”