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.

S100 calcium-binding protein A9 (S100A9), is elevated in plasma and bronchoalveolar lavage fluid (BALF) of COPD patients and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared to young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or inhibited activity with paquinimod, and exposed the models to chronic cigarette smoke S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and FEV0.05/FVC, compared to age-matched wild type or vehicle administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK, and c-RAF phosphorylation, MMP-3, MMP-9, MCP-1, IL-6, and KC release into the airways. Paquinimod administered to non-smoked aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor, LY3214996, or the c-RAF inhibitor, GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing TLR4, RAGE or EMMPRIN prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke and age-related COPD.

Chronic rhinosinusitis (CRS) is a common condition associated with inflammation and tissue remodeling of the nose and paranasal sinuses, frequently occurring with nasal polyps and allergies. Here we investigate inflammation and the protease profile in nasal tissues and plasma from control non-CRS patients and CRS patients. Gene expression for several cytokines, proteases, and antiproteases was quantified in nasal tissue from non-CRS and CRS subjects with nasal polyps. Elevated expression of S100A9, IL1A, MMP3, MMP7, MMP11, MMP25, MMP28, and CTSK was observed in tissue from CRS subjects with nasal polyps compared to control tissue. Tissue protein analysis confirmed elevated levels of these targets compared to controls, and increased MMP3 and MMP7 observed in CRS subjects with nasal polyps compared to CRS subjects without polyps. Plasma concentrations of MMP3 and MMP7 were elevated in the CRS groups compared to controls. The nasal cell line, CCL-30, was exposed to S100A9 protein, resulting in increased MMP3, MMP7, and CTSK gene expression and elevated proliferation. Silencing MMP3 significantly reduced S100A9-mediated cell proliferation. Therefore, the elevated expression of S100A9 and MMPs are observed in CRS nasal tissue and S100A9 stimulated MMP3 responses to contribute to elevated nasal cell proliferation.