Pulmonary pathology
Introduction
In this era of molecular biology, great strides have been made in elucidating the control mechanisms of the basic biological processes that contribute to lung development. Although many gaps in our knowledge remain, several aspects of cell and tissue differentiation, branching and maturation, as they pertain to the growth of airways, vessels and alveoli are now understood. In the newborn lung, much is also known about the intricate mechanisms involved in maintaining lung homeostasis. Despite these successes, respiratory disease continues to claim the lives of newborns. This chapter will describe several recently recognised conditions that can present in the neonatal period. The goal is to provide a roadmap for the studies that can be done to establish the diagnosis of a potentially fatal newborn lung disorder. These studies are also of import for the family and future siblings because some of these disorders are genetically transmitted. Furthermore, biopsy or autopsy provides an excellent opportunity to develop an archival tissue bank for molecular studies that will become possible as additional genetic secrets are unravelled.
The autopsy investigation of a respiratory death in a newborn is challenging. The clinical course provides a clue as to the line of investigation to be pursued. For example, prematurity, mechanical ventilatory support and oxygen therapy suggest hyaline membrane disease and bronchopulmonary dysplasia. A term infant who develops intractable respiratory distress shortly after birth raises the suspicion of conditions such as meconium aspiration, pneumonia, persistent pulmonary hypertension of the newborn, pneumothorax, cystic adenomatoid malformation and alveolar proteinosis or a surfactant protein deficiency. A clinical course characterised by severe hypoxaemia and pulmonary hypertension should include in the differential diagnosis a developmental disorder of the lung's vasculature. Of course, imaging studies aid in suggesting an aetiology. An analysis of all the causes of a respiratory death in a newborn is beyond the scope of this chapter. The disorders that will be discussed are recently recognised entities and fall into two broad categories for which the pathological change involves: (1) airspaces or alveolar septa or (2) the lung's vascular tree. Under (1) will be considered inherited disorders of surfactant proteins, granulocyte-macrophage colony stimulating factor (GM-CSF) and its receptor, while under (2) alveolar capillary dysplasia and misalignment of veins will be discussed. A final section will recount molecular studies that have demonstrated a genetic influence upon susceptibility to lung disease.
Section snippets
Inherited disorders of lung homeostasis
The distal airspaces in the lung are lined by pneumocytes designated as Type I and Type II. The Type II pneumocytes produce surfactant, a lipoprotein complex essential for normal lung function. The lipids are secreted into the airspace in the form of lamellar bodies and comprise mainly the phospholipid dipalmitoylphatidylcholine (DPPC). Within the airspace, the lamellar bodies undergo transformation into a lattice structure, tubular myelin, from which the surface-active monolayer is formed at
Alveolar capillary dysplasia and misalignment of pulmonary veins
Another entity that can cause severe neonatal respiratory distress accompanied by hypoxaemia and pulmonary hypertension is the rare disorder of lung vascular development—alveolar capillary dysplasia (ACD)—which may be associated with misalignment of pulmonary veins (MPV). Firstly, a brief review of the pulmonary vascular system is in order. The lung has a double arterial supply, the pulmonary arteries, which travel in the bronchovascular sheath in the centre of the lung lobules and conduct
Application of genomics and proteomics to the diagnosis of neonatal lung disease
The examples of SP-B deficiency and GM-CSF or GM-CSF receptor deficiency serve to illustrate the ability of genomics and proteomics to unravel the mysteries of what has hitherto been a black box. Congenital alveolar proteinosis (CAP) was a recognised entity for several decades, but the aetiology was unknown. It was modern molecular techniques that uncovered deficiency of SP-B and GM-CSF or its receptor among the underlying causes of CAP. Doubtless, additional causes of CAP will be identified in
Acknowledgements
This study was supported in part by grants from the NIH no. 55600 and from the Fleur-de-Lis Foundation of Cardinal Glennon Children's Hospital.
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2009, Biophysical JournalCitation Excerpt :These proteins, each constituting <1% by mass of surfactant, facilitate rapid movement of surfactant phospholipids to spaces close to the air-liquid interface and their efficient transfer from bilayers to the interface. Lack of, or alteration in, surfactant is associated with severe respiratory pathologies (4). Pulmonary surfactant films are particularly enriched in phospholipid species bearing saturated acyl chains, such as dipalmitoylphosphatidylcholine (DPPC), which accounts for ∼40% of surfactant by mass in most animal species (5).