The role of Lung Surfactant (LS) in lowering the surface tension, ?, at the alveolar air-liquid interface is well known. A second essential function of LS is to prevent the Laplace instability, which drives gas out of smaller alveoli and into larger ones, leading to alveolar de-recruitment, atelectasis and loss of lung compliance. These are the core symptoms of Acute Respiratory Distress Syndrome (ARDS), which afflicts 150,000 people in the US with a 40% mortality rate. To quantify the factors leading to the Laplace instability, I will examine the dilatational modulus, ? = ?(?????), which relates the change in surface tension, ?, to the change in interfacial area, A, as the interface is oscillated at breathing frequencies. For 2?-? > 0, the Laplace pressure decreases with decreasing radius, suppressing the Laplace Instability. However, if 2?-? < 0, variations in lung inflation drive the collapse of smaller alveoli, leading to decreased lung compliance and other symptoms of ARDS. We hypothesize that ARDS is exacerbated by the competitive adsorption of serum proteins and lysolipids, which increase in the alveolar fluids during ARDS-induced inflammation. These soluble inhibitors increase ? and also are theorized to dramatically decrease the dilatational modulus due to their diffusional exchange with the alveolar fluids, especially at low breathing frequencies. Such conditions arise in damaged areas of the lung with poor gas exchange and high levels of inflammation products and provoke the Laplace instability as 2?-? < 0. This leads to further damage in injured areas of the lung and a negative feedback loop is established that may be responsible for the ineffectiveness of current ARDS treatments. To address this hypothesis, I will use a novel capillary pressure microtensiometer to measure ?(?) of LS, serum proteins, and lysolipids for the first time. I will map out ? for clinical and model lung surfactants as a function of surfactant composition, morphology, surface pressure and frequency to determine the effects of saturated vs. unsaturated lipid fraction, domain morphology, and lung surfactant proteins SP-B and SP-C, cholesterol and fatty acid fractions. I will examine how e changes due to subphase compositions of lysolipids, albumin, and fibrinogen, all of which have elevated levels in the ARDS lung. These first of their kind measurements should provide a map of the conditions under which the Laplace instability plays a role in the progression of ARDS. Reversing the Laplace instability requires removing inhibitors that do adsorb. From our new understanding of e we will create LS formulations with optimized rheological properties to promote LS respreading via the Marangoni effect. We also propose that minimizing the anionic lipid fraction in LS and adding low concentrations of polyethylene glycol (PEG) and trivalent cations from adjuvants such as alum, will provide an electrostatic and osmotic assist to promote LS adsorption. Maximizing LS adsorption relative to serum proteins and lysolipids would lower g, increase e and reverse the conditions leading to the Laplace instability, thereby restoring proper lung function.
) Our work is designed to understand the origins of surfactant inhibition in acute lung injury and acute respiratory distress syndrome in children and adults which affects more than 150,000 per year with > 40% mortality rates. Our goal is to develop composition-function relationships to determine the dynamics and monolayer organization of synthetic replacement lung surfactants to provide better treatments for ARDS.
