Comparison of different dosing strategies of intratracheally instilled budesonide on meconium injured piglet lungs

Lin, Chi-Yi; Jeng, Mei Jy; Yang, Yi; Hsiao, Yu Hsuan; Kou, Yu Ru

doi:10.1002/ppul.23697

Cited by 8 publications

(13 citation statements)

References 31 publications

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“…Many studies quantified cytokines/chemokines, such as IL-1β, IL-6, IL-8, and TNF-α (Table 11) all of which largely depend on pattern recognition by the Toll-like receptor family (especially TLR4/MD-2, CD14, and C5a) (Salvesen et al, 2010). Specific therapy assessment to influence e.g., CD14 (Thomas et al, 2018) and downstream NF-κB by broad-acting glucocorticoids (Holopainen et al, 2001; Lin et al, 2016, 2017) or more specific inhibitors of NF-κB are scarce and deserve further evaluation.…”

Section: Resultsmentioning

confidence: 99%

An Unsettled Promise: The Newborn Piglet Model of Neonatal Acute Respiratory Distress Syndrome (NARDS). Physiologic Data and Systematic Review

2019

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Despite great advances in mechanical ventilation and surfactant administration for the newborn infant with life-threatening respiratory failure no specific therapies are currently established to tackle major pro-inflammatory pathways. The susceptibility of the newborn infant with neonatal acute respiratory distress syndrome (NARDS) to exogenous surfactant is linked with a suppression of most of the immunologic responses by the innate immune system, however, additional corticosteroids applied in any severe pediatric lung disease with inflammatory background do not reduce morbidity or mortality and may even cause harm. Thus, the neonatal piglet model of acute lung injury serves as an excellent model to study respiratory failure and is the preferred animal model for reasons of availability, body size, similarities of porcine and human lung, robustness, and costs. In addition, similarities to the human toll-like receptor 4, the existence of intraalveolar macrophages, the sensitivity to lipopolysaccharide, and the production of nitric oxide make the piglet indispensable in anti-inflammatory research. Here we present the physiologic and immunologic data of newborn piglets from three trials involving acute lung injury secondary to repeated airway lavage (and others), mechanical ventilation, and a specific anti-inflammatory intervention via the intratracheal route using surfactant as a carrier substance. The physiologic data from many organ systems of the newborn piglet—but with preference on the lung—are presented here differentiating between baseline data from the uninjured piglet, the impact of acute lung injury on various parameters (24 h), and the follow up data after 72 h of mechanical ventilation. Data from the control group and the intervention groups are listed separately or combined. A systematic review of the newborn piglet meconium aspiration model and the repeated airway lavage model is finally presented. While many studies assessed lung injury scores, leukocyte infiltration, and protein/cytokine concentrations in bronchoalveolar fluid, a systematic approach to tackle major upstream pro-inflammatory pathways of the innate immune system is still in the fledgling stages. For the sake of newborn infants with life-threatening NARDS the newborn piglet model still is an unsettled promise offering many options to conquer neonatal physiology/immunology and to establish potent treatment modalities.

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Section: Resultsmentioning

confidence: 99%

An Unsettled Promise: The Newborn Piglet Model of Neonatal Acute Respiratory Distress Syndrome (NARDS). Physiologic Data and Systematic Review

2019

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“…4,5,7 To avoid the side effects of systemic steroid, [10][11][12] several investigators advocated the use of intratracheal steroid for the treatment of ALI or PARDS. [13][14][15][16][17][18] However, surfactant deficiency may lead to alveolar collapse and diffuse lung atelectasis, 7,19 which hinders the uniform distribution of drug within the lungs and reduces the efficacy of local steroid treatment. Surfactant is a surface tension-lowering agent that has been widely used to treat surfactant-deficiency lung diseases or PARDS.…”

Section: Discussionmentioning

confidence: 99%

“…Steroid has been long considered a classical therapy for neonatal ARDS due to its anti-inflammatory effect; however, the side effects of systemic steroids remain a major concern. [10][11][12] For the prevention of side effects, several animal or clinical studies used intratracheal instillation 13,14 or inhalation [15][16][17][18] of steroids for the treatment of meconium aspiration syndrome (MAS) or prevention of bronchopulmonary dysplasia (BPD) and other respiratory morbidities. However, the local treatment with steroids remains challenging particularly in surfactant-deficiency lungs with alveolar collapse and diffuse atelectasis, which is a common problem in preterm infants 7,19 .…”

mentioning

confidence: 99%

Efficacy of Intratracheal Budesonide-Surfactant Combined Therapy in Surfactant-Insufficient Rat Lungs with Lipopolysaccharide Insult

Tsao

Lin

Lee

et al. 2021

Preprint

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Objectives: Intratracheal steroid therapy for lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains challenging particularly in surfactant-deficiency lungs, a common problem of preterm infants. Surfactant has been used as a vehicle for intratracheal steroid in the treatment of other types of ALI. This study investigated the efficacy of intratracheal budesonide (BUD) delivered by two concentrations of surfactant in the treatment of LPS-induced ALI in surfactant-insufficiency rat lungs. Methods: Male adult rats were anesthetized and ventilated. Our ALI model was established by repeated saline lavage to produce surfactant insufficiency, followed by intratracheal LPS instillation. Five study groups (n=5 for each) with different intratracheal treatments following ALI were used: Control (no treatment), BUD (IT-NS-BUD; BUD in saline); IT-DS-BUD (BUD in diluted surfactant); IT-FS-BUD (BUD in full-strength surfactant); IT-FS (full-strength surfactant). Cardiopulmonary variables were monitored 4 h post injury. Histological and immunohistochemical assessments of the lungs were performed. Results: The IT-FS-BUD and IT-FS groups presented better gas exchange, less metabolic acidosis, less oxygen index, and more stable hemodynamic changes than the IT-DS-BUD, IT-NS-BUD, and Control groups. The total lung injury scores assessed by histological examination were ordered as follows: IT-FS-BUD < IT-DS-BUD or IT-FS < IT-NS-BUD < Control. The immunostaining intensities of lung myeloperoxidase showed the following order: IT-NS-BUD, IT-DS-BUD, or IT-FS-BUD < Control or IT-FS. Only the IT-FS-BUD group displayed a smaller immunostaining intensity of lung TNF-α than the control group. Conclusion: Among our therapeutic strategies, intratracheal BUD delivered by full-strength surfactant confers an optimal protection against LPS-induced ALI in surfactant-insufficiency rat lungs.

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“…In our laboratory, we had analyzed different methods of anti‐inflammatory treatment to treat severe meconium‐injured lungs, including IV or intratracheal corticosteroids and SL combined with intratracheal corticosteroids. Although we found some beneficial effects, they are not good enough 9,14,22 . Therefore, we made more efforts to evaluate other potentially effective anti‐inflammatory therapeutic methods.…”

Section: Introductionmentioning

confidence: 86%

Pathophysiological effects of intravenous phosphodiesterase type 4 inhibitor in addition to surfactant lavage in meconium‐injured newborn piglet lungs

Chen

Lin

Lee

et al. 2020

Pediatric Pulmonology

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Background Nonsteroidal anti‐inflammatory drugs, such as selective phosphodiesterase type 4 (PDE4) inhibitors have potential anti‐inflammatory and respiratory smooth muscle relaxation effects. This study aimed to investigate the pathophysiological effects of an intravenous PDE4 inhibitor (rolipram) and surfactant lavage (SL) in a newborn piglet model of meconium aspiration syndrome (MAS). Methods MAS was induced in 25 newborn piglets, which were randomly divided into control and four SL treatment groups administered with different doses of intravenous rolipram (0, 0.1, 0.5, and 1 mg/kg). Cardiopulmonary variables were monitored and recorded. The experimental time was 4 hours. Serial blood was drawn for blood gas and biomarker analyses. Lung tissue was examined for histological analysis. Results All SL‐treated groups revealed improved oxygenation during the 4‐hour experiments and had significantly lower peak inspiratory pressure levels than the control group at the end of experiments. All SL plus rolipram‐treated groups exhibited significantly higher lung compliance than the control group. However, the animals receiving high‐dose (0.5 and 1.0 mg/kg) rolipram demonstrated significantly elevated heart rates. Lung histology of the nondependent sites revealed significantly lower lung injury scores in all SL‐treated groups compared with that in the control group, but there were no differences among the rolipram‐treated groups. Conclusions In addition to SL, intravenous PDE4 inhibitors may further improve lung compliance in treating MAS; however, it is necessary to consider cardiovascular adverse effects, primarily tachycardia. Further investigations are required before the clinical application of intravenous PDE4 inhibitor as an anti‐inflammatory agent to treat severe MAS.

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Comparison of different dosing strategies of intratracheally instilled budesonide on meconium injured piglet lungs

Abstract: IT instillation of one dose of 0.5 mg/kg budesonide is beneficial in treating meconium-injured piglet lungs during the first 8 h of injury, but a second dose at an interval of 4 h does not have a superior beneficial effect compared to one dose.

Cited by 8 publications

References 31 publications

An Unsettled Promise: The Newborn Piglet Model of Neonatal Acute Respiratory Distress Syndrome (NARDS). Physiologic Data and Systematic Review

An Unsettled Promise: The Newborn Piglet Model of Neonatal Acute Respiratory Distress Syndrome (NARDS). Physiologic Data and Systematic Review

Efficacy of Intratracheal Budesonide-Surfactant Combined Therapy in Surfactant-Insufficient Rat Lungs with Lipopolysaccharide Insult

Pathophysiological effects of intravenous phosphodiesterase type 4 inhibitor in addition to surfactant lavage in meconium‐injured newborn piglet lungs

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