chapter  5
18 Pages

Structure– Function Relationships of Hydrophobic Proteins SP-B and SP-C in Pulmonary Surfactant

ByJesu´s Pe´rez-Gil, Antonio Cruz, and Ine´s Plasencia

I. Introduction 125

II. Evolutionary Origin of Hydrophobic Pulmonary

Surfactant Proteins 126

III. Biological vs. Clinical Engineering of Pulmonary Surfactant 127

IV. Structure-Function Relationships of SP-B 128

V. Structure-Function Relationships of SP-C 132

Acknowledgments 136

References 136

I. Introduction

Decades of research on pulmonary surfactant resulted in a serious paradox that

was not resolved until the mid-1980s. Seminal physiological studies had demon-

strated that lack of surfactant in premature babies was the primary cause of res-

piratory distress syndrome associated with high morbidity and mortality. In

addition, several research groups had shown that administration of an exogenous

surfactant material early after birth of premature animals could prevent and

largely reduce respiratory complications. Suspensions prepared using material

extracted with organic solvents from animal lungs were very efficient as exogen-

ous surfactant. Such organic extractions are routine for separation of the lipid

moiety from biological samples, and hence lipids were soon recognized as

essential components for the biophysical function of surfactant in the lungs.

Extensive physicochemical studies from the early seventies established that the

lipid composition of pulmonary surfactant appeared particularly well suited to

reach and sustain very low surface tensions at low lung volumes during breathing.

The main surface-active molecule in surfactant is a disaturated lecithin, dipal-

mitoylphosphatidylcholine (DPPC), whereas other lipid species are important

to fluidize DPPC enough to facilitate its adsorption at physiological temperature

into the air-liquid interface of lungs. The paradox was that no mixture of purely

synthetic lipids mimicking the composition of natural surfactant worked equally

well in vivo as exogenous surfactant. The key finding that allowed further under-

standing was the discovery of hydrophobic surfactant-associated proteins, now

called SP-B and SP-C. These polypeptides are so hydrophobic that co-isolate

with lipids in organic solvent extractions. On the other hand, they have low anti-

genicity and are not easily identified in routine protein assays. Therefore, until the

1980s, it was unrecognized that these proteins were present in surfactant lipid