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.

<p>Insights into Chronic Obstructive Pulmonary Disease as Critical Risk Factor for Cardiovascular Disease</p>

“…SPD is predominantly produced in type 2 pneumocytes and is also expressed in the endothelium of the cardiovascular system, acting as a mediator on inflammatory signals. 40 SPD has been associated in longitudinal studies with an increase of cardiovascular mortality in COPD patients. 41 CC-16 are secreted mainly in the terminal portion of the bronchioles and their plasma levels are inversely associated with an increase in mortality in COPD.…”

Influence of Concomitant Arterial Hypertension on Activity of Inflammatory Process in Patients With Community-Acquired Pneumonia

“…Thus, in patients with the first group in all three observation points, the data obtained were higher relative to the levels of SP-D of the second group, which is related to the influence of hypertension as a factor that characterizes the higher severity of the systemic and local inflammatory response during acute processes, defining injuries pulmonary tissue [19]. The study by Grith L Sorensen and co-authors showed the presence of SP-D in endothelial cells and its involvement in modulating the local inflammatory response [20], which in turn indicates the feedback of the effect of the development of the process of inflammation in the lungs caused by bacterial agents [21] on the possible complications of concomitant arterial hypertension.…”

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

“…Several lung diseases like-asthma, acute respiratory distress syndrome (ARDS), COPD etc. are reported to be associated with aberration in the functionalities of surfactant proteins [70,106]. In SARS-CoV-2 affected lung, production of the surfactant proteins are found to be deregulated (Figure 8) Considering all these, lung surfactants might be useful in the treatment of COVID-19 patients, as lung surfactant replacement therapies were previously reported to be successful in other respiratory infections and acute lung injury to reduce the lung damage of the patients [104,108,109] and also our analysis found it as an alternative from enrichment of related process deregulated genes (data not shown).…”

“…Host miRNAs miR-421 are found to be downregulating LMCD1; while miR-137, miR-375, miR-429 fail to modulate CCDC59 and GATA6 because of their probable inactivation/suppression by differential expression of its regulating TFs (Figure 8). As SFTPD and SFTPC are downregulated along with several regulatory partners, their primary function of immunomodulation and efficient air exchange in lung [68,69] might be seriously hindered by the viral proteins; which could further lead to abnormal pathogenic lung injury [70].…”