Abstract
The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.
Highlights
Introduction toS100 ProteinsIn multiple diseases, numerous exogenous and endogenous factors trigger inflammatory cascades
It is suggested that the term “damage-associated molecular patterns (DAMPs)” is too broad of a term to characterize all endogenous molecules linked to an inflammatory pathway; there is an ongoing debate on defining DAMPs and classifying them [2]
The S100A8/A9 complex is expressed in tuberculosis (TB) [113,114,115], as S100A8/A9-expressing neutrophils are observed to assemble in granulomas and S100A8/A9 levels correlated with active disease [113]
Summary
Numerous exogenous and endogenous factors trigger inflammatory cascades. S100 proteins act as DAMP molecules and can work as stimulatory ligands for both immune and nonimmune cells, such as endothelial cells [13] They do so by binding pattern recognition receptors (PRRs) such as toll-like receptor 4 (TLR4) as well as non-PRR DAMP receptors such as advanced glycation end products (RAGE) [14]. By binding to these receptors, S100 proteins trigger downstream nuclear factor-κB (NF-κB), which results in upregulation of the proinflammatory gene expression [15, 16]. We outline potential therapeutic approaches to treat pulmonary diseases by targeting S100 proteins
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