Lung surfactant function inhibition leading to decreased lung function

Inhalation of substances, chemicals, particles and mixtures is the main route of occupational exposure. This adverse outcome pathway (AOP) describes the connections between the inhibition of lung surfactant function, and how this is connected to decreased lung function. Lung surfactant is a thin layer of lipids and proteins that lines the respiratory parts of the lungs. Decreased lung function in humans is characterized by symptoms such as coughing, difficult breathing, tightness in the chest, fever and vomiting (AO) [1, 2]. In experimental animals acute inhalation toxicity is defined as the total of adverse effects caused by a substance following a single uninterrupted exposure by inhalation over a short period of time (24 hours or less) to a substance capable of being inhaled [3]. This AOP describes one of the pathways that can lead to decreased lung function seen as respiratory clinical signs of toxicity in humans and experimental animals.

The main function of lung surfactant is to lower the surface tension at the air-liquid interface during the breathing cycle. Inhaling substances that reach the alveoli can potentially interact with and inhibit the lung surfactant function (MIE). Inhibition leads to an increase in minimum surface tension and alveolar collapse (KE1), the individual alveoli can stay closed or be open again by the force of the inhaled air. If the alveolus stays closed, this reduces the tidal volume (KE3), reducing the area for gas exchange in the lungs and reduces blood oxygenation (hypoxemia). If the alveolus reopens, this can lead to loss of capillary membrane integrity due to shear stress on the epithelium (KE2) and bleeding into the lungs. Blood components (such as albumin and fibrin) reaching the air-liquid interface will further disrupt lung surfactant function by interacting with the lung surfactant (feedback loop between KE2 and MIE) [4-7] leading to the exacerbation of the process. The combination of alveolar collapse, loss of capillary membrane integrity and reduced tidal volume leads to decreased lung function. The MIE (lung surfactant function inhibition) can be examined in vitro by measuring the effect of a substance or mixture of substances on the lung surfactant function. The effects of blood entering the lung and interacting with lung surfactant can likewise be studied in the in vitro assay. Reduced tidal volume can be measured in vivo, using experimental animals in whole body plethysmographs that are exposed to the substance in question, while monitoring respiration parameters. The effect of reduced tidal volume, hypoxemia, can be measured by analysing the oxygenation of the blood both from experimental animals, and patients that have inhaled substances leading to immediate adverse lung effects. The loss of capillary membrane integrity can be examined in experimental animals, by analysing liquid flushed from the lungs (broncho-alveolar lavage), and in lavage from patients undergoing examination during acute lung injury [8].   

Decreased lung function is observed frequently in humans [2]. Similar symptoms are seen in experimental animals [1]. Lung surfactant function impairment in vitro has been strongly associated with induction of acute lung toxicity both in humans and in experimental animals [1].

In addition to lung surfactant function impairment, there are potentially several other pathways leading to decreased lung function, e.g. inflammatory cells activation, activation of the immune system, damage to the epithelial cells of the lungs, interaction with the nervous system in the lungs; however other AOPs may describe this process, and can be linked to this proposed AOP. Additionally decreased lung function may have long term effects on the lungs, such as development of fibrosis (AOP 173) or asthma and COPD (AOP 196 and AOP 148).

1. Sørli, J.B., et al., Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition. ALTEX, 2017. 35(1): p. 26-36.
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3. OECD (2018). "Guidance document on inhalation toxicity studies series on testing and assessment No. 39 (Second Edition)."
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7. Zuo, Y.Y., et al., Chitosan enhances the in vitro surface activity of dilute lung surfactant preparations and resists albumin-induced inactivation. Pediatr. Res, 2006. 60(2): p. 125-130.
8. Nakos, G., et al., Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med, 1998. 24(4): p. 296-303.