**3. Impact of Inhaled Particle Deposition in Lung Surfactant Film**

The transport of inhaled particles along the respiratory tract involves several processes: Brownian diffusion, gravitational sedimentation, inertial impaction, and interception [114]. However, the specific role of each individual process is far from clear due to the high complexity of the breathing dynamics. On the other side, inhaled aerosols commonly present a high polydispersity, which limits their penetration into deep lung regions, and only a small fraction of particles with sizes below 4 μm can go through the respiratory airways to reach the alveolar cavity. This can be understood considering the tortuous way, including 23 tubular bifurcations, encountered for the particle from their inhalation through the nose to their final destination inside the alveoli [7].

It is commonly accepted that the biophysical effects of inhaled substances start when they penetrate into the alveoli, leading to a partial inhibition of the LS function, and in turn in the lung function [32]. It should be stressed that the high surface area of the alveoli (up to 100 m2) leads to relatively small concentrations of deposited particles on the alveolar fluid. However, the high surface-to-volume (or surface-to-mass) ratio of deposited particles leads to a situation in which inhaled particles induce stronger effects than those that are expected considering only the deposited mass, i.e., the acquired dose [42,55,57,65,115,116]. Therefore, the evaluation of the safety of inhaled particles must consider the role of several parameters, including the dimensions of the particulate material and its concentration, the particle molecular structure, and other physico-chemical properties (hydrophobicity and charge) [69,114,117–125].

It should be stressed that the deposition of particles on the LS layer is commonly associated with several events that are triggered after the interaction of the particles with the LS. Such interaction may occur directly with specific components of the LS film at the interface, or indirectly through the competition of the inhaled particles with the LS components for the space available at the interface [63,126–129]. Thus, the interaction of particles with the LS film may induce an inhibition of the LS functionality. In particular, particles can critically impact normal respiratory function [66], with the alteration of the Marangoni flows occurring in the LS upon particle deposition playing a critical role [130,131]. This is particularly important because Marangoni flows are essential in the control of the compositional remodeling of the LS film during breathing. Therefore, if the Young–Laplace law is assumed as an oversimplified representation of the alveolar mechanics during breathing [132], it may be expected that an alveolar compression under high surface tension conditions may induce an alveolar collapse. However, the ability of LS to decrease the surface tension during exhalation, and the consequent reduction of the respiratory work, takes the system far from collapse conditions. This is, in part, a result of the high content of LS in DPPC, and other disaturated phospholipids, which lead to the formation, at room temperature, of highly condensed phase with thigh packing at very low surface tensions. However, the incorporation of particles into the LS film may influence the mechanical aspects associated with the normal physiological respiratory function in different ways [32,65,66].

The deposition of particles on the LS film may inhibit the formation of condensed phases during alveolar compression, which in turn limits its ability to reduce the surface tension, and drives a premature alveolar collapse, e.g., hydrophobic particles may remain trapped within the hydrophobic regions of the LS film, modifying the intricate balance of the interactions emerging between the components and hindering the formation of tightly packed phases [133,134]. This can lead to a situation in which the surface tension is not low enough during compression, and it is impossible to overcome the forces pulling the alveolar walls together [135]. It should be noted that collapsed alveoli can be reopened during inspiration. However, alveolar collapse leads to a reduction of the tidal volume [32]. On the other side, particle incorporation modifies the remodeling dynamics of LS film, modifying the area of the hysteresis loop corresponding to the compression-expansion cycles. This is the result of the modification of the boundary conditions controlling the mass transport between the interfacial film and the adjacent fluid due to two possible

effects: (i) incomplete clearance of inhaled particles from LS film or (ii) modification of the fluid phase composition as a result of the expulsion of particles from the interface during the compression [130,131,136–138]. The latter effect adds an additional mechanism in which particles can influence the functionality of LS as a result of the adsorption of LS compounds onto the particle surface, contributing to the formation of an LS corona onto particle surface which influence their fate. This modifies the particle wettability and the LS composition, which alters the ability of LS to reduce the surface tension and the remodeling process [139]. It is commonly accepted that SP-A binds to hydrophilic particles, facilitating the subsequent adsorption of the rest of the LS components, which allows particle clearance from the lung [140]. The situation changes when hydrophobic particles are considered, with the binding of hydrophobic components starting the formation of the corona [141]. According to the above discussion, it may be expected that particles penetrating into the alveolar cavity can be embedded within the LS membrane and undergo different processes in a highly dynamic environment. Thus, particles will be subjected to the same compression-expansion processes than the LS film, which can induce their release from the LS towards the alveolar spaces, making it possible for particles to interact and be internalized by the cellular barrier [142,143]. Therefore, it may be expected that particle inhalation can present short-term and long-term harmful effects in the normal physiology of the respiratory process.
