IMMUNOREGULATORY FUNCTIONS OF SURFACTANT PROTEINS
Jo Rae Wright
Abstract | Because the lungs function as the body’s gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response thatcould damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.
A disease that affects premature newborns, resulting in increased difficulty in breathing. The disease is caused by a lack of surfactant, which helps to keep the lungs from collapsing.
Box 3709, 438 Nanaline Duke Building, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. e-mail: j.wright@cellbio. duke.edu
The surfacearea of the lung is expansive — approximately the size of a tennis court. The extremely thin, delicate gas-exchanging epithelium of this large organ allows efficient diffusion of oxygen and carbon dioxide between inspired air and the pulmonary circulation. The average person inhales about 10,000 litres of gas per day; this gas is laden with bacteria, viruses, oxidants, pollutants and allergens.Fortunately, several immune mechanisms function in the lung to help maintain its sterility. When a non-immune host is challenged, innate immunity responds swiftly, often without invoking an inflammatory response. The innate immune components in the lung include the following: mucus, which provides a physical barrier that coats the airway epithelium and can be thought of as a ‘mucociliary escalator’that moves particles up to the mouth, where they can be swallowed; opsonins, such as immunoglobulins and complement; and phagocytic cells, such as alveolar macrophages and neutrophils (FIG. 1). Pulmonary surfactant proteins are components of the lung innate immune system that have been identified relatively recently and are the focus of this review. Pulmonary surfactant was initially identified asa lipoprotein complex that reduces surface tension at the air–liquid interface of the lung1,2. This definition has been reassessed in light of recent studies that show that surfactant also functions in pulmonary host defence and that surfactant proteins are expressed in non-pulmonary sites.
Surfactant is mostly composed of phospholipids that are essential for reducing surface tension at theair–liquid interface of the lung. About 10% of surfactant consists of protein; four surfactant proteins have been defined: SP-A, SP-B, SP-C and SP-D. SP-B and SP-C are small and extremely hydrophobic. SP-B is essential for the ability of surfactant to reduce surface tension3, and SP-C has recently been shown to bind lipopolysaccharide (LPS)4,5. In the absence of surfactant, surface tension isextremely high at end expiration and tends to collapse the lung. This makes breathing difficult to the extent that respiration is frequently impossible without ventilatory support and surfactant replacement. A deficiency of surfactant — which can result in RESPIRATORY-DISTRESS SYNDROME — occurs when infants are born prematurely, before their surfactant biosynthetic machinery has matured. Treatment ofthese babies with exogenous surfactant replacement (BOX 1) reduces mortality and morbidity due to this disease. A similar clinical presentation also occurs in fullterm babies who have lethal genetic mutations in SP-B 3 or in the lipid transporter ABCA3 (ATP-binding cassette, subfamily A, member 3)6; surfactant-replacement therapy is ineffective in these babies. In addition, mutations in SP-C have...