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Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2‐agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2‐related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β 2 -agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E 2 -related EP 2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E 2 (PGE 2 ) and the cell softening was abolished when EP 4 receptors for PGE 2 were antagonized. Elevated levels of PGE 2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E 2 and its EP 2 and EP 4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

A thin film of pulmonary surfactant lines the surface of the airways and alveoli, where it lowers the surface tension in the peripheral lungs, preventing collapse of the bronchioles and alveoli and reducing the work of breathing. It also possesses a barrier function for maintaining the blood-gas interface of the lungs and plays an important role in innate immunity. The surfactant film covers the epithelium lining both large and small airways, forming the first line of defense between toxic airborne particles/pathogens and the lungs. Furthermore, surfactant has been shown to relax airway smooth muscle (ASM) after exposure to ASM agonists, suggesting a more subtle function. Whether surfactant masks irritant sensory receptors or interacts with one of them is not known. The relaxant effect of surfactant on ASM is absent in bronchial tissues denuded of an epithelial layer. Blocking of prostanoid synthesis inhibits the relaxant function of surfactant, indicating that prostanoids might be involved. Another possibility for surfactant to be active, namely through ATP-dependent potassium channels and the cAMP-regulated epithelial chloride channels [cystic fibrosis transmembrane conductance regulators (CFTRs)], was tested but could not be confirmed. Hence, this review discusses the mechanisms of known and potential relaxant effects of pulmonary surfactant on ASM. This review summarizes what is known about the role of surfactant in smooth muscle physiology and explores the scientific questions and studies needed to fully understand how surfactant helps maintain the delicate balance between relaxant and constrictor needs.

Purpose: Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants., Methods: This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf ® , both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated., Results: Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls., Conclusions: This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects., (© 2024. The Author(s).)

Bronchial asthma is an extremely heterogenous chronic respiratory disorder with several distinct endotypes and phenotypes. These subtypes differ not only in the pathophysiological changes and/or clinical features but also in their response to the treatment. Therefore, precise diagnostics represent a fundamental condition for effective therapy. In the diagnostic process, metabolomic approaches have been increasingly used, providing detailed information on the metabolic alterations associated with human asthma. Further information is brought by metabolomic analysis of samples obtained from animal models. This article summarizes the current knowledge on metabolomic changes in human and animal studies of asthma and reveals that alterations in lipid metabolism, amino acid metabolism, purine metabolism, glycolysis and the tricarboxylic acid cycle found in the animal studies resemble, to a large extent, the changes found in human patients with asthma. The findings indicate that, despite the limitations of animal modeling in asthma, pre-clinical testing and metabolomic analysis of animal samples may, together with metabolomic analysis of human samples, contribute to a novel way of personalized treatment of asthma patients.

Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury., Competing Interests: Conflicts of interest The authors declare no conflicts of interest in relation to this article, (Copyright © 2023 Elsevier B.V. All rights reserved.)

N -acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders.

Inhalation of silica particles causes inflammatory changes leading to fibrotizing silicosis. Considering a lack of effective therapy, and a growing information on the wide actions of green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), the aim of this study was to evaluate the early effects of EGCG on markers of inflammation and lung fibrosis in silicotic rats. The silicosis model was induced by a single transoral intratracheal instillation of silica (50 mg/mL/animal), while controls received an equivalent volume of saline. The treatment with intraperitoneal EGCG (20 mg/kg, or saline in controls) was initiated the next day after silica instillation and was given twice a week. Animals were euthanized 14 or 28 days after the treatment onset, and the total and differential counts of leukocytes in the blood and bronchoalveolar lavage fluid (BALF), wet/dry lung weight ratio, and markers of inflammation, oxidative stress, and fibrosis in the lung were determined. The presence of collagen and smooth muscle mass in the walls of bronchioles and lung vessels was investigated immunohistochemically. Early treatment with EGCG showed some potential to alleviate inflammation, and a trend to decrease oxidative stress-induced changes, including apoptosis, and a prevention of fibrotic changes in the bronchioles and pulmonary vessels. However, further investigations should be undertaken to elucidate the effects of EGCG in the lung silicosis model in more detail. In addition, because of insufficient data from EGCG delivery in silicosis, the positive and eventual adverse effects of this herbal compound should be carefully studied before any preventive use or therapy with EGCG may be recommended.

Treatment of acute respiratory distress syndrome (ARDS) is challenging due to its multifactorial aetiology. The benefit of antioxidant therapy was not consistently demonstrated by previous studies. We evaluated the effect of two different doses of intravenous (i.v.) N -acetylcysteine (NAC) on oxidative stress, inflammation and lung functions in the animal model of severe LPS-induced lung injury requiring mechanical ventilation. Adult Wistar rats with LPS (500 μg/kg; 2.2 mL/kg) were treated with i.v. NAC 10 mg/kg (NAC10) or 20 mg/kg (NAC20). Controls received saline. Lung functions, lung oedema, total white blood cell (WBC) count and neutrophils count in blood and bronchoalveolar lavage fluid, and tissue damage in homogenized lung were evaluated. NAC significantly improved ventilatory parameters and oxygenation, reduced lung oedema, WBC migration and alleviated oxidative stress and inflammation. NAC20 in comparison to NAC10 was more effective in reduction of oxidative damage of lipids and proteins, and inflammation almost to the baseline. In conclusion, LPS-instilled and mechanically ventilated rats may be a suitable model of ARDS to test the treatment effects at organ, systemic, cellular and molecular levels. The results together with literary data support the potential of NAC in ARDS.