Abstract
Surfactant protein C (SP-C) is an important player in enhancing the interfacial adsorption of lung surfactant lipid films to the alveolar air-liquid interface. Doing so, surface tension drops down enough to stabilize alveoli and the lung, reducing the work of breathing. In addition, it has been shown that SP-C counteracts the deleterious effect of high amounts of cholesterol in the surfactant lipid films. On its side, cholesterol is a well-known modulator of the biophysical properties of biological membranes and it has been proven that it activates the inflammasome pathways in the lung. Even though the molecular mechanism is not known, there are evidences suggesting that these two molecules may interplay with each other in order to keep the proper function of the lung. This review focuses in the role of SP-C and cholesterol in the development of lung fibrosis and the potential pathways in which impairment of both molecules leads to aberrant lung repair, and therefore impaired alveolar dynamics. From molecular to cellular mechanisms to evidences in animal models and human diseases. The evidences revised here highlight a potential SP-C/cholesterol axis as target for the treatment of lung fibrosis.
Highlights
While surfactant protein C (SP-C) deficiency mediated surfactant dysfunction and impaired lung mechanics are likely contributors in the generation of local mechanical stresses and strains, its biophysical interplay with cholesterol on the one hand, and its modulation of Tolllike receptor 4 (TLR-4) signaling on the other hand, highlights SP-C as a key element in a complex profibrotic network
Thereby SP-C deficiency comes into play in animal models, and in patients with familial and non-familial forms of lung fibrosis such as idiopathic pulmonary fibrosis (IPF)
Further research is needed in order to determine the potential of cholesterol lowering drugs as treatment or combined with anti-fibrotic drugs to find a better therapy for IPF patients
Summary
As recently reviewed by Zuniga-Hertz and Patel (2019), 2.32 billion years ago, the atmospheric oxygen raised (Bekker et al, 2004) leading to many changes in life. The main function of lung surfactant is to reduce surface tension in order to prevent alveolar collapse during expiration and stabilizing open alveoli allowing oxygen to diffuse through the lung tissue to the blood (Knudsen et al, 2017; Bates and Smith, 2018; Knudsen and Ochs, 2018). Collapsed airways require high amounts of energy to be reopened, while dysfunctional surfactant increases the hysteresis effect in inflating lungs by rising surface tension This effect results in parenchymal stiffening, increasing levels of pulmonary tissue elastance (Smith et al, 2013; Birkelbach et al, 2015). This work emphasized aberrant tissue hysteresivity (the quotient of energy dissipative forces and lung elastance) at low PEEP, a condition where alveoli are prone to collapse At those low lung volumes, surfactant becomes the major defining factor of pulmonary breathing mechanics (Bachofen et al, 1987). Phenomena described in a number of children suffering interstitial lung disease (chILD), who showed reduced or absent levels of mature SP-C (Cong et al, 2017), as described
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