RARE DISEASE
Chronic respiratory distress with surfactant metabolism deficiency
Chronic respiratory distress with surfactant metabolism deficiency
Chronic respiratory distress with surfactant metabolism deficiency
Drug discovery
1
drug
With orphan designation
Overview
Chronic respiratory distress with surfactant metabolism deficiency (CRD-SMD) is a rare genetic interstitial lung disease caused by mutations in surfactant-related genes (SFTPB, SFTPC, ABCA3) [1][4][6]. It manifests variably, from neonatal respiratory failure in severe SP-B deficiency to chronic interstitial lung disease with cough, tachypnea, hypoxia, and failure to thrive in children/adults [4][6]. Diagnosis combines genetic testing, imaging (ground-glass opacities, cysts), and histopathology showing alveolar damage, fibrosis, and foamy macrophages [4][18].
Categories: rare genetic diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
85 drug discovery papers about Chronic respiratory distress with surfactant metabolism deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
85 drug discovery papers about Chronic respiratory distress with surfactant metabolism deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-07-06 | Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
Abstract Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. Graphical Abstract
2023-02-02 | Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages
Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease.Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis.However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown.Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE + ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE + ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs).We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE + ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs.We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE + ADEs supplementation.Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE + ADEs.The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders.STIMATE + ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca 2+ responsiveness and long-term Ca 2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection.This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding.In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE + ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.
2022-11-01 | Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D
Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects.The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury.First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis.The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis.The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.
2022-09-26 | PGC-1α activity and mitochondrial dysfunction in preterm infants
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
2019-02-10 | Phospholipid Remodeling in Physiology and Disease
Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands’ cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.
proteins
2023-11-23 | Surfactant as a drug carrier
Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The inherent chemical properties of surfactant allows it to readily distribute throughout the respiratory system. Therapeutic agents delivered by surfactant can primarily confer additional benefits but have potential to improve the surfactant function. It is critically important that additional agents do not interefere with the innate surface tension lowering function of surfactant. Systemic evaluation through benchtop, translational and human trials to translate this potential technique into clinical practice.
2022-02-01 | Pulmonary surfactant as a versatile biomaterial to fight COVID-19
The COVID-19 pandemic has wielded an enormous pressure on global health care systems, economics and politics. Ongoing vaccination campaigns effectively attenuate viral spreading, leading to a reduction of infected individuals, hospitalizations and mortality. Nevertheless, the development of safe and effective vaccines as well as their global deployment is time-consuming and challenging. In addition, such preventive measures have no effect on already infected individuals and can show reduced efficacy against SARS-CoV-2 variants that escape vaccine-induced host immune responses. Therefore, it is crucial to continue the development of specific COVID-19 targeting therapeutics, including small molecular drugs, antibodies and nucleic acids. However, despite clear advantages of local drug delivery to the lung, inhalation therapy of such antivirals remains difficult. This review aims to highlight the potential of pulmonary surfactant (PS) in the treatment of COVID-19. Since SARS-CoV-2 infection can progress to COVID-19-related acute respiratory distress syndrome (CARDS), which is associated with PS deficiency and inflammation, replacement therapy with exogenous surfactant can be considered to counter lung dysfunction. In addition, due to its surface-active properties and membrane-interacting potential, PS can be repurposed to enhance drug spreading along the respiratory epithelium and to promote intracellular drug delivery. By merging these beneficial features, PS can be regarded as a versatile biomaterial to combat respiratory infections, in particular COVID-19.
2020-03-17 | Dose-Response Study on Surfactant Nebulization Therapy During Nasal Continuous Positive Airway Pressure Ventilation in Spontaneously Breathing Surfactant-Deficient Newborn Piglets*
Objectives: The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome–associated pathophysiology of the neonatal lungs. Design: Prospective, randomized, animal model study. Setting: An experimental laboratory. Subjects: Thirty-six newborn piglets. Interventions: Different doses (100, 200, 400, and 600 mg/kg) of poractant alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation–surfactant–extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets ( n = 6/group) with bronchoalveolar lavage–induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). Measurements and Main Results: Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized poractant alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. Conclusions: In newborn piglets with severe bronchoalveolar lavage–induced respiratory distress syndrome, our results demonstrate that the administration of nebulized poractant alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.
2020-01-30 | CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation
Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44-/- mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44-/- AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44-/- AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44-/- mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44-/- AMs. Oxidized phospholipids were more cytotoxic to CD44-/- AMs and induced greater lung inflammation in CD44-/- mice. Reconstitution of CD44+/+ mice with CD44-/- bone marrow as well as adoptive transfer of CD44-/- AMs into CD44+/+ mice showed that lipid accumulation in CD44-/- AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44-/- mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44-/- AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44-/- AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.
2018-12-01 | Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins
Pulmonary surfactant (PS) has been extensively studied because of its primary role in mammalian breathing. The deposition of this surface-active material at the alveolar air-water interface is essential to lower surface tension, thus avoiding alveolar collapse during expiration. In addition, PS is involved in host defense, facilitating the clearance of potentially harmful particulates. PS has a unique composition, including 92% of lipids and 8% of surfactant proteins (SPs) by mass. Although they constitute the minor fraction, SPs to a large extent orchestrate PS-related functions. PS contains four surfactant proteins (SPs) that can be structurally and functionally divided in two groups, i.e. the large hydrophilic SP-A and SP-D and the smaller hydrophobic SP-B and SP-C. The former belong to the family of collectins and are involved in opsonization processes, thus promoting uptake of pathogens and (nano)particles by phagocytic cell types. The latter SPs regulate interfacial surfactant adsorption dynamics, facilitating (phospho)lipid transfer and membrane fusion processes. In the context of pulmonary drug delivery, the exploitation of PS as a carrier to promote drug spreading along the alveolar interface is gaining interest. In addition, recent studies investigated the interaction of PS with drug-loaded nanoparticles (nanomedicines) following pulmonary administration, which strongly influences their biological fate, drug delivery efficiency and toxicological profile. Interestingly, the specific biophysical mode-of-action of the four SPs affect the drug delivery process of nanomedicines both on the extra-and intracellular level, modulating pulmonary distribution, cell targeting and intracellular delivery. This knowledge can be harnessed to exploit SPs for the design of unique and bio-inspired drug delivery strategies.
gene therapies
2022-01-14 | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction
Pulmonary surfactant is critically important to prevent atelectasis by lowering the surface tension of the alveolar lining liquid. While respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of pulmonary surfactant including surfactant protein B (SP-B, SFTPB gene), surfactant protein C (SP-C, SFTPC gene), and the ATP-Binding Cassette transporter A3 (ABCA3, ABCA3 gene) result in severe neonatal RDS or childhood interstitial lung disease (chILD). These proteins play essential roles in pulmonary surfactant biogenesis and are expressed in alveolar epithelial type II cells (AEC2), the progenitor cell of the alveolar epithelium. SP-B deficiency most commonly presents in the neonatal period with severe RDS and requires lung transplantation for survival. SFTPC mutations act in an autosomal dominant fashion and more commonly presents with chILD or idiopathic pulmonary fibrosis than neonatal RDS. ABCA3 deficiency often presents as neonatal RDS or chILD. Gene therapy is a promising option to treat monogenic lung diseases. Successes and challenges in developing gene therapies for genetic disorders of surfactant dysfunction include viral vector design and tropism for target cell types. In this review, we explore adeno-associated virus (AAV), lentiviral, and adenoviral (Ad)-based vectors as delivery vehicles. Both gene addition and gene editing strategies are compared to best design treatments for lung diseases resulting from pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes .
2007-08-16 | Gene delivery by the hSP-B promoter to lung alveolar type II epithelial cells in LAL-knockout mice through bone marrow mesenchymal stem cells
Tissue damage and inflammation promote bone marrow stem cells (BMSCs) to differentiate into a variety of cell types in residing tissues. BMSCs can stably maintain their plasticity and are an ideal cell population for delivery of therapeutic genes to non-hematopoietic tissues. Using lacZ as a reporter gene, we demonstrated that the lung-specific human surfactant protein B (hSP-B) 1.5-kb promoter is able to deliver the lacZ gene into the lung of lysosomal acid lipase (LAL) gene-knockout (lal−/−) mice by β-galactosidase staining, flow cytometry and double immunofluorescence staining. Around 10–18% alveolar type II epithelial cells (AT II cells) exhibited positive lacZ gene expression after 8 weeks of BMSC injection in recipient lal−/− mice. The wild-type mice exhibited no expression after the same treatment. BMSCs from hSP-B 1.5-kb lacZ transgenic mice entered and repopulated in lal−/− bone marrow. The study supports a concept that pulmonary inflammation caused by LAL deficiency can trigger BMSC residing in lal−/− bone marrow, migrating into the lung and converting into residential AT II cells. The hSP-B 1.5 kb promoter is an ideal tool to deliver therapeutic genes into AT II cells through BMSCs to cure pulmonary inflammation-triggered diseases.
2004-01-01 | Surfactant Protein B Deficiency in Infants With Respiratory Failure
Surfactant Protein B (SP-B) deficiency has been recently identified as an uncommon, autosomal recessive lung disorder in term infants. This inability to produce SP-B leads to progressive, lethal, hypoxemic respiratory failure in the first year of life. A frameshift mutation (121 ins 2) is the predominant but not exclusive cause. The clue to diagnosis is to have a high suspicion of SP-B deficiency in any term infant with severe respiratory distress without any apparent cause. SP-B deficiency can be diagnosed prenatally or postnatally. The only current treatment options available include lung transplantation or compassionate care. Current developments in gene therapy offer hope for future treatment.
cell therapies
2024-03-01 | A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic
Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic–ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.
2020-07-14 | Recent advances in understanding and management of bronchopulmonary dysplasia
In the current era, the survival of extremely low-birth-weight infants has increased considerably because of new advances in technology; however, these infants often develop chronic dysfunction of the lung, which is called bronchopulmonary dysplasia (BPD). BPD remains an important cause of neonatal mortality and morbidity despite newer and gentler modes of ventilation. BPD results from the exposure of immature lungs to various antenatal and postnatal factors that lead to an impairment in lung development and aberrant growth of lung parenchyma and vasculature. However, we still struggle with a uniform definition for BPD that can help predict various short- and long-term pulmonary outcomes. With new research, our understanding of the pathobiology of this disease has evolved, and many new mechanisms of lung injury and repair are now known. By utilizing the novel ‘omic’ approaches in BPD, we have now identified various factors in the disease process that may act as novel therapeutic targets in the future. New investigational agents being explored for the management and prevention of BPD include mesenchymal stem cell therapy and insulin-like growth factor 1. Despite this, many questions remain unanswered and require further research to improve the outcomes of premature infants with BPD.
2016-10-28 | Long Term Culture of the A549 Cancer Cell Line Promotes Multilamellar Body Formation and Differentiation towards an Alveolar Type II Pneumocyte Phenotype
Pulmonary research requires models that represent the physiology of alveolar epithelium but concerns with reproducibility, consistency and the technical and ethical challenges of using primary or stem cells has resulted in widespread use of continuous cancer or other immortalized cell lines. The A549 ‘alveolar’ cell line has been available for over four decades but there is an inconsistent view as to its suitability as an appropriate model for primary alveolar type II (ATII) cells. Since most work with A549 cells involves short term culture of proliferating cells, we postulated that culture conditions that reduced proliferation of the cancer cells would promote a more differentiated ATII cell phenotype. We examined A549 cell growth in different media over long term culture and then used microarray analysis to investigate temporal regulation of pathways involved in cell cycle and ATII differentiation; we also made comparisons with gene expression in freshly isolated human ATII cells. Analyses indicated that long term culture in Ham’s F12 resulted in substantial modulation of cell cycle genes to result in a quiescent population of cells with significant up-regulation of autophagic, differentiation and lipidogenic pathways. There were also increased numbers of up- and down-regulated genes shared with primary cells suggesting adoption of ATII characteristics and multilamellar body (MLB) development. Subsequent Oil Red-O staining and Transmission Electron Microscopy confirmed MLB expression in the differentiated A549 cells. This work defines a set of conditions for promoting ATII differentiation characteristics in A549 cells that may be advantageous for studies with this cell line.
small molecules
2024-07-06 | Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
Abstract Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. Graphical Abstract
2023-02-02 | Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages
Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease.Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis.However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown.Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE + ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE + ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs).We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE + ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs.We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE + ADEs supplementation.Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE + ADEs.The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders.STIMATE + ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca 2+ responsiveness and long-term Ca 2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection.This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding.In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE + ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.
2022-11-01 | Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D
Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects.The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury.First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis.The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis.The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.
2022-09-26 | PGC-1α activity and mitochondrial dysfunction in preterm infants
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
2019-02-10 | Phospholipid Remodeling in Physiology and Disease
Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands’ cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.
proteins
2023-11-23 | Surfactant as a drug carrier
Drug delivery using a surfactant vehicle has the potential to prevent systemic side effects by delivering therapeutic agents directly to the respiratory system. The inherent chemical properties of surfactant allows it to readily distribute throughout the respiratory system. Therapeutic agents delivered by surfactant can primarily confer additional benefits but have potential to improve the surfactant function. It is critically important that additional agents do not interefere with the innate surface tension lowering function of surfactant. Systemic evaluation through benchtop, translational and human trials to translate this potential technique into clinical practice.
2022-02-01 | Pulmonary surfactant as a versatile biomaterial to fight COVID-19
The COVID-19 pandemic has wielded an enormous pressure on global health care systems, economics and politics. Ongoing vaccination campaigns effectively attenuate viral spreading, leading to a reduction of infected individuals, hospitalizations and mortality. Nevertheless, the development of safe and effective vaccines as well as their global deployment is time-consuming and challenging. In addition, such preventive measures have no effect on already infected individuals and can show reduced efficacy against SARS-CoV-2 variants that escape vaccine-induced host immune responses. Therefore, it is crucial to continue the development of specific COVID-19 targeting therapeutics, including small molecular drugs, antibodies and nucleic acids. However, despite clear advantages of local drug delivery to the lung, inhalation therapy of such antivirals remains difficult. This review aims to highlight the potential of pulmonary surfactant (PS) in the treatment of COVID-19. Since SARS-CoV-2 infection can progress to COVID-19-related acute respiratory distress syndrome (CARDS), which is associated with PS deficiency and inflammation, replacement therapy with exogenous surfactant can be considered to counter lung dysfunction. In addition, due to its surface-active properties and membrane-interacting potential, PS can be repurposed to enhance drug spreading along the respiratory epithelium and to promote intracellular drug delivery. By merging these beneficial features, PS can be regarded as a versatile biomaterial to combat respiratory infections, in particular COVID-19.
2020-03-17 | Dose-Response Study on Surfactant Nebulization Therapy During Nasal Continuous Positive Airway Pressure Ventilation in Spontaneously Breathing Surfactant-Deficient Newborn Piglets*
Objectives: The current clinical treatment of neonates with respiratory distress syndrome includes endotracheal intubation and intratracheal instillation of exogenous surfactant. Nebulization of surfactant offers an attractive alternative. The aims of this study were to test nebulization as a noninvasive method of administering surfactant and determine the optimal dose for the treatment of respiratory distress syndrome–associated pathophysiology of the neonatal lungs. Design: Prospective, randomized, animal model study. Setting: An experimental laboratory. Subjects: Thirty-six newborn piglets. Interventions: Different doses (100, 200, 400, and 600 mg/kg) of poractant alfa were administered via a vibrating membrane nebulizer (eFlow-Neos; Pari Pharma GmbH, Starnberg, Germany) or a bolus administration using the intubation–surfactant–extubation (Insure) technique (200 mg/kg) to spontaneously breathing newborn piglets ( n = 6/group) with bronchoalveolar lavage–induced respiratory distress syndrome during nasal continuous positive airway pressure (180 min). Measurements and Main Results: Pulmonary, hemodynamic, and cerebral effects were assessed. Histologic analysis of lung and brain tissue was also performed. After repeated bronchoalveolar lavage, newborn piglets developed severe respiratory distress syndrome. Rapid improvement in pulmonary status was observed in the Insure group, whereas a dose-response effect was observed in nebulized surfactant groups. Nebulized poractant alfa was more effective at doses higher than 100 mg/kg and was associated with similar pulmonary, hemodynamic, and cerebral behavior to that in the Insure group, but improved lung injury scores. Conclusions: In newborn piglets with severe bronchoalveolar lavage–induced respiratory distress syndrome, our results demonstrate that the administration of nebulized poractant alfa using an investigational customized eFlow-Neos nebulizer is an effective and safe noninvasive surfactant administration technique.
2020-01-30 | CD44 Loss Disrupts Lung Lipid Surfactant Homeostasis and Exacerbates Oxidized Lipid-Induced Lung Inflammation
Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44-/- mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44-/- AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44-/- AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44-/- mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44-/- AMs. Oxidized phospholipids were more cytotoxic to CD44-/- AMs and induced greater lung inflammation in CD44-/- mice. Reconstitution of CD44+/+ mice with CD44-/- bone marrow as well as adoptive transfer of CD44-/- AMs into CD44+/+ mice showed that lipid accumulation in CD44-/- AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44-/- mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44-/- AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44-/- AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.
2018-12-01 | Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins
Pulmonary surfactant (PS) has been extensively studied because of its primary role in mammalian breathing. The deposition of this surface-active material at the alveolar air-water interface is essential to lower surface tension, thus avoiding alveolar collapse during expiration. In addition, PS is involved in host defense, facilitating the clearance of potentially harmful particulates. PS has a unique composition, including 92% of lipids and 8% of surfactant proteins (SPs) by mass. Although they constitute the minor fraction, SPs to a large extent orchestrate PS-related functions. PS contains four surfactant proteins (SPs) that can be structurally and functionally divided in two groups, i.e. the large hydrophilic SP-A and SP-D and the smaller hydrophobic SP-B and SP-C. The former belong to the family of collectins and are involved in opsonization processes, thus promoting uptake of pathogens and (nano)particles by phagocytic cell types. The latter SPs regulate interfacial surfactant adsorption dynamics, facilitating (phospho)lipid transfer and membrane fusion processes. In the context of pulmonary drug delivery, the exploitation of PS as a carrier to promote drug spreading along the alveolar interface is gaining interest. In addition, recent studies investigated the interaction of PS with drug-loaded nanoparticles (nanomedicines) following pulmonary administration, which strongly influences their biological fate, drug delivery efficiency and toxicological profile. Interestingly, the specific biophysical mode-of-action of the four SPs affect the drug delivery process of nanomedicines both on the extra-and intracellular level, modulating pulmonary distribution, cell targeting and intracellular delivery. This knowledge can be harnessed to exploit SPs for the design of unique and bio-inspired drug delivery strategies.
gene therapies
2022-01-14 | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction
Pulmonary surfactant is critically important to prevent atelectasis by lowering the surface tension of the alveolar lining liquid. While respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of pulmonary surfactant including surfactant protein B (SP-B, SFTPB gene), surfactant protein C (SP-C, SFTPC gene), and the ATP-Binding Cassette transporter A3 (ABCA3, ABCA3 gene) result in severe neonatal RDS or childhood interstitial lung disease (chILD). These proteins play essential roles in pulmonary surfactant biogenesis and are expressed in alveolar epithelial type II cells (AEC2), the progenitor cell of the alveolar epithelium. SP-B deficiency most commonly presents in the neonatal period with severe RDS and requires lung transplantation for survival. SFTPC mutations act in an autosomal dominant fashion and more commonly presents with chILD or idiopathic pulmonary fibrosis than neonatal RDS. ABCA3 deficiency often presents as neonatal RDS or chILD. Gene therapy is a promising option to treat monogenic lung diseases. Successes and challenges in developing gene therapies for genetic disorders of surfactant dysfunction include viral vector design and tropism for target cell types. In this review, we explore adeno-associated virus (AAV), lentiviral, and adenoviral (Ad)-based vectors as delivery vehicles. Both gene addition and gene editing strategies are compared to best design treatments for lung diseases resulting from pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes .
2007-08-16 | Gene delivery by the hSP-B promoter to lung alveolar type II epithelial cells in LAL-knockout mice through bone marrow mesenchymal stem cells
Tissue damage and inflammation promote bone marrow stem cells (BMSCs) to differentiate into a variety of cell types in residing tissues. BMSCs can stably maintain their plasticity and are an ideal cell population for delivery of therapeutic genes to non-hematopoietic tissues. Using lacZ as a reporter gene, we demonstrated that the lung-specific human surfactant protein B (hSP-B) 1.5-kb promoter is able to deliver the lacZ gene into the lung of lysosomal acid lipase (LAL) gene-knockout (lal−/−) mice by β-galactosidase staining, flow cytometry and double immunofluorescence staining. Around 10–18% alveolar type II epithelial cells (AT II cells) exhibited positive lacZ gene expression after 8 weeks of BMSC injection in recipient lal−/− mice. The wild-type mice exhibited no expression after the same treatment. BMSCs from hSP-B 1.5-kb lacZ transgenic mice entered and repopulated in lal−/− bone marrow. The study supports a concept that pulmonary inflammation caused by LAL deficiency can trigger BMSC residing in lal−/− bone marrow, migrating into the lung and converting into residential AT II cells. The hSP-B 1.5 kb promoter is an ideal tool to deliver therapeutic genes into AT II cells through BMSCs to cure pulmonary inflammation-triggered diseases.
2004-01-01 | Surfactant Protein B Deficiency in Infants With Respiratory Failure
Surfactant Protein B (SP-B) deficiency has been recently identified as an uncommon, autosomal recessive lung disorder in term infants. This inability to produce SP-B leads to progressive, lethal, hypoxemic respiratory failure in the first year of life. A frameshift mutation (121 ins 2) is the predominant but not exclusive cause. The clue to diagnosis is to have a high suspicion of SP-B deficiency in any term infant with severe respiratory distress without any apparent cause. SP-B deficiency can be diagnosed prenatally or postnatally. The only current treatment options available include lung transplantation or compassionate care. Current developments in gene therapy offer hope for future treatment.
cell therapies
2024-03-01 | A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic
Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic–ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.
2020-07-14 | Recent advances in understanding and management of bronchopulmonary dysplasia
In the current era, the survival of extremely low-birth-weight infants has increased considerably because of new advances in technology; however, these infants often develop chronic dysfunction of the lung, which is called bronchopulmonary dysplasia (BPD). BPD remains an important cause of neonatal mortality and morbidity despite newer and gentler modes of ventilation. BPD results from the exposure of immature lungs to various antenatal and postnatal factors that lead to an impairment in lung development and aberrant growth of lung parenchyma and vasculature. However, we still struggle with a uniform definition for BPD that can help predict various short- and long-term pulmonary outcomes. With new research, our understanding of the pathobiology of this disease has evolved, and many new mechanisms of lung injury and repair are now known. By utilizing the novel ‘omic’ approaches in BPD, we have now identified various factors in the disease process that may act as novel therapeutic targets in the future. New investigational agents being explored for the management and prevention of BPD include mesenchymal stem cell therapy and insulin-like growth factor 1. Despite this, many questions remain unanswered and require further research to improve the outcomes of premature infants with BPD.
2016-10-28 | Long Term Culture of the A549 Cancer Cell Line Promotes Multilamellar Body Formation and Differentiation towards an Alveolar Type II Pneumocyte Phenotype
Pulmonary research requires models that represent the physiology of alveolar epithelium but concerns with reproducibility, consistency and the technical and ethical challenges of using primary or stem cells has resulted in widespread use of continuous cancer or other immortalized cell lines. The A549 ‘alveolar’ cell line has been available for over four decades but there is an inconsistent view as to its suitability as an appropriate model for primary alveolar type II (ATII) cells. Since most work with A549 cells involves short term culture of proliferating cells, we postulated that culture conditions that reduced proliferation of the cancer cells would promote a more differentiated ATII cell phenotype. We examined A549 cell growth in different media over long term culture and then used microarray analysis to investigate temporal regulation of pathways involved in cell cycle and ATII differentiation; we also made comparisons with gene expression in freshly isolated human ATII cells. Analyses indicated that long term culture in Ham’s F12 resulted in substantial modulation of cell cycle genes to result in a quiescent population of cells with significant up-regulation of autophagic, differentiation and lipidogenic pathways. There were also increased numbers of up- and down-regulated genes shared with primary cells suggesting adoption of ATII characteristics and multilamellar body (MLB) development. Subsequent Oil Red-O staining and Transmission Electron Microscopy confirmed MLB expression in the differentiated A549 cells. This work defines a set of conditions for promoting ATII differentiation characteristics in A549 cells that may be advantageous for studies with this cell line.
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Drug Discovery Landscape
1 orphan drug designation for Chronic respiratory distress with surfactant metabolism deficiency.
1 orphan drug designation for Chronic respiratory distress with surfactant metabolism deficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Bovactant | small molecules | EMA | Aerogen Pharma Limited |
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