Respiratory distress syndrome (RDS) was once the leading cause of death in live‐born premature infants in the U.S., accounting for ~ 10,000 deaths per year. Today, RDS is an uncommon cause of neonatal mortality in developed nations because it can be successfully treated. The history of RDS research is a splendid example of how investigator‐initiated multidisciplinary research drives medical progress.

RDS is sometimes referred to as hyaline membrane disease because at autopsy the lungs contain protein aggregates that form membranes in the distal airways. However, the most significant autopsy finding is severe atelectasis. Pediatricians had long recognized that the condition of RDS patients deteriorated as the extent of atelectasis increased. Ultimately the oxygenation oftissues became inadequate and death resulted from multiorgan system failure. The question was: “Why did the lungs of premature infants progressively become airless”?

Physiologists and anatomists had speculated for decades about the effects of surface tension in the air spaces of the lung. The pulmonary alveolus is a roughly spherical structure whose surface is a curved gas‐liquid interface with physical properties that approximately fit the Law of Laplace: p = 2T/R, where p = pressure difference across the surface, T = surface tension, and R = radius of curvature. This predicts an instability of the pulmonary alveolus: if surface tension remains constant then the decrease in alveolar size upon expiration would increase intra‐alveolar pressure, promoting further decrease in alveolar size as residual air was forced into more proximal airway spaces. To account for observed stability of normal pulmonary alveoli, a surfactant capable of reducing alveolar surface tension was proposed but never demonstrated. In 1955, Pattle (1) published results of experiments on the stability of bubbles produced in various fluids including serum and pulmonary edema fluid (PEF). He observed a remarkable stability of the bubbles present in PEF, and concluded that the bubbles contained “a protein layer that can abolish the tension of the alveolar surface”. Further insight into the pathogenesis of RDS came from Gruenwald (2) who concluded that the major resistance to the expansion of RDS lungs during inspiration was alveolar surface tension. Clements demonstrated the presence of a surface tension reducing material in lung extracts not present in serum or other tissues (3). Notably, Clements initially encountered great difficulty getting this discovery published. His findings led to the discovery by Avery and Mead (4) that surfactant was absent from the lungs of infants who died with RDS, while it was in the lungs of infants who died of nonpulmonary disease, provided their birth weight was greater than 1 kg.

This created widespread interest in determining the chemical composition of surfactant, with the goal of developing a replacement therapy. Mammalian surfactant is ~ 92% lipid and 8% protein. Phosphatidylcholine species account for ~70% of the lipid, and the predominant compound is dipalmitoylphosphatidyl‐choline (DPPC). There are four constituent proteins in natural surfactant: SP‐A, SP‐B, SP‐C, and SP‐D. DPPC reduces surface tension at the air‐water interface in the alveolus to near zero. However, DPPC alone is a poor surfactant; at 37°C it’s a solid and cannot adsorb to a surface. The hydrophobic SP‐B and SP‐C promote the surface adsorption of DPPC and are necessary for normal surfactant activity. Approximately 10% of surfactant lipids are the acidic phospholipids phosphati‐dylglycerol and phosphatidylinositol. Proportions of these compounds change during fetal lung development, and this characteristic is the basis ofa clinical test routinely performed on amniotic fluid to determine when lung maturation is sufficient to allow delivery without the development of RDS.

To prevent alveolar collapse, one strategy was to provide the missing surfactant. A second was to develop a respirator that while regulating inspiratory and expiratory airflow would also maintain positive pressure in the alveoli at the end of the expiratory phase. Used together, these therapies are highly effective.

Basic research that reversed the dismal prognosis of infants with RDS led to the discovery of additional surfactant functions. Upon determining their molecular structures it became clear that SP‐A and SP‐D belonged to the Collectin family of glycoproteins. It is now established that SP‐A binds endotoxin and a wide range of gram‐positive and gram‐negative organisms, promoting phagocytosis and killing of microbes by alveolar macrophages. In solving the pathogenesis of RDS an entirely new set of questions were generated, the answers to which will likely provide new insights into the physiology and pathology of the lung.