Surfactant Protein D in Respiratory and Non-Respiratory Diseases

Abstract

Surfactant protein D (SP-D) is a multimeric collectin that is involved in innate immune defense and expressed in pulmonary, as well as non-pulmonary, epithelia. SP-D exerts antimicrobial effects and dampens inflammation through direct microbial interactions and modulation of host cell responses via a series of cellular receptors. However, low protein concentrations, genetic variation, biochemical modification, and proteolytic breakdown can induce decomposition of multimeric SP-D into low-molecular weight forms, which may induce pro-inflammatory SP-D signaling. Multimeric SP-D can decompose into trimeric SP-D, and this process, and total SP-D levels, are partly determined by variation within the SP-D gene, SFTPD. SP-D has been implicated in the development of respiratory diseases including respiratory distress syndrome, bronchopulmonary dysplasia, allergic asthma, and chronic obstructive pulmonary disease. Disease-induced breakdown or modifications of SP-D facilitate its systemic leakage from the lung, and circulatory SP-D is a promising biomarker for lung injury. Moreover, studies in preclinical animal models have demonstrated that local pulmonary treatment with recombinant SP-D is beneficial in these diseases. In recent years, SP-D has been shown to exert antimicrobial and anti-inflammatory effects in various non-pulmonary organs and to have effects on lipid metabolism and pro-inflammatory effects in vessel walls, which enhance the risk of atherosclerosis. A common SFTPD polymorphism is associated with atherosclerosis and diabetes, and SP-D has been associated with metabolic disorders because of its effects in the endothelium and adipocytes and its obesity-dampening properties. This review summarizes and discusses the reported genetic associations of SP-D with disease and the clinical utility of circulating SP-D for respiratory disease prognosis. Moreover, basic research on the mechanistic links between SP-D and respiratory, cardiovascular, and metabolic diseases is summarized. Perspectives on the development of SP-D therapy are addressed.

Keywords: allergic asthma; atherosclerosis; chronic obstructive lung disease; respiratory distress syndrome; surfactant protein D.

Figure 1

Multimerization of surfactant protein D (SP-D). (A) Regions of the trimeric SP-D subunit. The subunit structure has been drawn to the approximate dimensions of the protein domains. Adapted with permission from Ref. (190). (B) Multimerization of the trimeric SP-D subunit (3 chains) into 4-subunit cruciform (12 chains) or fuzziball >4-subunit (>12 chains) structures of SP-D. (C) Schematic overview of how multimeric SP-D is implicated in antimicrobial defense. Binding of multimeric SP-D to microbe-associated glycans may block interaction of the microbe with its receptors, aggregate the microbes, or SP-D may act as an opsonin, enhancing endocytic uptake of the microbe in host cells. Only fuzziball SP-D multimers are shown for simplicity. CTLD, C-type lectin domain.

Figure 2

Circulatory spill-over of pulmonary surfactant protein D (SP-D) in inflammatory disease. SP-D is synthesized by Club cells, type II alveolar cells, and endothelial cells, and the levels of SP-D multimers and trimers in the serum are highly genetically determined. In the inflamed lung, the production of trimeric SP-D is increased, due to various chemical modifications and proteolytic breakdown of the protein, and loss of air–blood barrier integrity allows spill-over of pulmonary SP-D into the circulation. For simplicity, only alveolar damage is illustrated. Moreover, only fuzziball SP-D multimers are depicted.

Figure 3

Surfactant protein D (SP-D)-mediated effects in experimental allergic asthma. The overview of cellular functions in allergic asthma was inspired by Lambrecht and Hammad (347) and Fahy (357). The multiple effects of SP-D include (1) removal of allergens by induction of aggregation and accelerating their binding and uptake by alveolar macrophages (92, 154, 358); (2) suppression of M2 macrophage polarization and allergen-stimulated macrophage NO production (123, 352); (3) inhibition of IgE binding to allergens, blocking allergen-induced histamine release by basophils and degranulation by mast cells (153, 154); (4) suppression of peripheral blood mononuclear cell interleukin (IL)-2 secretion (146), lymphocyte proliferation (358), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-dependent induction of apoptosis (145). SP-D-mediated T-cell responses are CTLA4 dependent (149); (5) decreased lymphocyte IL-4 and IL-13 release (221); (6) suppression of eosinophil chemotaxis and degranulation, and induction of apoptosis (142, 143); (7) SP-D increases allergen interaction with respiratory epithelium, yet dampens epithelial chemotactic signaling (161); (8) SP-D increases uptake and removal of allergens in macrophages (93); (9) the overall effects of SP-D in allergic asthma in vivo include dampening of eosinophilia, alveolar macrophage accumulation, increased specific antibody levels, airway hyperreactivity, subepithelial fibrosis, and mucous metaplasia. These are features, which have either been observed in Sftpd^−/− mice or that are subjected to phenotype rescue by endogenous SP-D, or administration of recombinant SP-D/60-kDa recombinant trimeric fragment of SP-D lacking the N-terminal but retaining a part of the collagen region (, , , , , , , –353, 359). Leakage of pulmonary SP-D to the circulation in allergic asthma has been demonstrated in clinical samples (19). Only trimeric SP-D and fuzziball SP-D multimers are shown for simplicity.

Figure 4

Surfactant protein D (SP-D)-mediated effects in experimental pulmonary inflammation and airspace enlargement in chronic obstructive pulmonary disease (COPD). The overview of cellular functions in COPD was inspired by Barnes (408) and Brusselle et al. (407). Multiple effects of endogenous or exogenous SP-D include (1) suppression of inflammation elicited by noxious stimuli (395, 400, 402, 409). The SP-D-mediated mechanisms includes SP-Ds interaction with immune-regulatory receptors (117, 134, 170, 174, 177), depression of oxidative stress, including iNOS activity, protection of phospholipid oxidation (, –413); (2) decrease of macrophage transforming growth factor-β (TGF-β) production and fibrocyte recruitment (163). These SP-D effects may partly enable suppression of age-induced influences; (3) increased septal wall thickening by fibrotic deposition (194, 397); (4) airspace enlargement and loss of surface area of alveolar epithelia (194, 202, 397, 414); (5) suppression of the production of ROS and NO by macrophages, and possibly additional cell types (125, 194, 395, 409, 411). Fibrotic and emphysematic changes in the lung may also depend on inhibition of iNOS by SP-D (397, 413). (5/6) SP-D suppresses metalloproteinase production in alveolar macrophages (125, 194) and putatively additional cell types. The result is an overall decrease in pulmonary protease activity via oxidant-sensitive pathways (125, 194); (7) prolonged alveolar epithelial cell and macrophage survival after cigarette smoke extract exposure or oxidative stress (276, 410); (8) increased efferocytosis (94, 121, 170, 201, 415); (9) opsonization of microbes for phagocytosis (91). (10) The resulting effects of SP-D relevant for COPD-like phenotypes in vivo include dampening of chronic low-level pulmonary inflammation predominantly mediated by macrophages and correlated with reduced oxidative stress and protease activity (125, 194), which can prevent changes in pulmonary elastance due to both tissue breakdown and fibrotic build up that occur sequentially with increasing age and exposure to noxious stimuli (395, 397, 409, 413). Leakage of pulmonary SP-D to the circulation in COPD has been demonstrated using clinical samples (280). Only trimeric SP-D and fuzziball SP-D multimers are shown for simplicity.

Figure 5

Surfactant protein D (SP-D)-mediated effects in atherogenesis. The simplified overview of cellular functions in atherogenesis was inspired by Skaggs et al. (458). Effects of SP-D in a long-term diet-induced model of atherosclerosis include (1) repression of high-density lipoprotein (HDL)-cholesterol levels (48) and also additional plasma lipid levels in a genetic model (457); (2) model-dependent induction of tumor necrosis factor-α (TNF-α) in vivo (48, 457) and TNF-α induction in monocytes in vitro, dependent on osteoclast-associated receptor (OSCAR) signaling (133); (3) induction of macrophage proliferation (457); (4) induction of circulating monocytes; (5) decreased coverage of smooth muscle in plaques (457); (6) the result is an overall increase in atherosclerotic plaque formation with accumulation of foam cells and cholesterol crystals, accompanied by disturbed plasma lipid levels in Sftpd^−/− mice compared with Sftpd^+/+ mice (48, 457). Moreover, TNF-α and NO increase endothelial SP-D expression (63) and circulating SP-D is increased in clinical cardiovascular disease (CVD) (25, 429). Only trimeric SP-D and fuzziball SP-D multimers are shown for simplicity.