Surfactant Protein Research Articles

Cortisol regulates neonatal lung development via Smoothened

BackgroundNeonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the corticosteroids remains largely unclear.MethodsIn this study, the simulation of the molecular docking by Autodock, in vitro binding experiments, and Sonic Hedgehog (SHH) pathway examination in cells were performed to study the directly binding of cortisol to Smoothened (SMO). To explore the effect of cortisol action on the SHH pathway on neonatal lung development, we generated a genetic mouse, in which leucine 116 (L112 in human) of SMO was mutated to alanine 116 (L116A, Smoa/a) by the CRISPR-Cas9, based on sequence differences between human and mice. Then, we performed morphological analysis, single-cell RNA sequencing (scRNA-seq) on lung tissue and fluorescence in situ hybridization (FISH).ResultsIn this study, we reported that cortisol, the endogenous glucocorticoid, inhibited the sonic hedgehog (Shh)/SMO-mediated proliferation of lung fibroblasts to maintain the normal lung development. Specifically, cortisol competed with cholesterol for binding to the cysteine-rich domain (CRD) in SMO to inhibit the activation of Shh/SMO signaling, a critical signaling known for cell proliferation. Cortisol did not inhibit the activation of SMO when L112 in its CRD was mutated to A112. Moreover, Smoa/a (L116A) mice exhibited the immature lungs in which over-proliferation of interstitial fibroblasts and reduction in the surfactant protein were evident.ConclusionTogether, these results suggested that cortisol regulated cholesterol stimulation of SMO by competitively binding to the CRD to regulate neonatal lung maturation in mice.

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression. In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders. We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (ΔKL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels. In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.

Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo. Here, we describe the development of mature, expandable AT2 organoids derived from human fetal lungs which are phenotypically stable, can differentiate into AT1-like cells, and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, demonstrating that their depletion phenocopies the pathological SFTPC redistribution seen for the SFTPC-I73T variant. In summary, we demonstrate the development of a novel alveolar organoid model and use it to identify effectors of SFTPC maturation necessary for AT2 health.

Effect of Surfactant Protein B and D Genes Polymorphisms on Frequency and Severity of Acute Bronchiolitis

Background and aim: Acute bronchiolitis (AB) is the most common cause of hospitalization in infants. Varying bronchiolitis presentations in patients with similar demographic characteristics suggest genetic causes of individual differences. Materials and Methods: The study included 106 infants diagnosed with AB and 107 healthy infants recruited from a pediatric outpatient clinic. Genotyping was conducted for intron 4 and C/A–18 in the SP-B gene, along with SP-D/160 (Ala160Thr) and SP-D/270 (Ser270Thr) polymorphisms in the SP-D gene. Results: The SP-B intron 4 invariant polymorphisms of ins/ins and ins/del were 93.40% and 4.72% in the AB group and 84.11% and 15.89% in the control group, respectively (p = 0.012). Frequency of polymorphism in the SP-D/270 (Ser270Thr) gene for Ser/Ser and Ser/Thr was 60% and 39.05% in the AB group and 79.44% and 18.69% in the control group, respectively (p = 0.004). The frequencies of Ser and Thr alleles were 79.90% and 20.10% in the AB group and 88.79% and 11.21% in the control group, respectively (p = 0.012). There was no observed correlation between the SP-B intron 4 and C/A-1, as well as the SP-D Ser270Thr and Ala160Thr polymorphisms, with the severity of AB (p > 0.05). Conclusion: SP-B gene polymorphisms were identified as risk factors for AB, while SP-D polymorphisms appeared to play a protective role. However, these polymorphisms were not linked to AB severity. Early identification of children at risk could enable close monitoring and preventive care.

Inhaled ozone induces distinct alterations in pulmonary function in models of acute and episodic exposure in female mice.

Ozone is an urban air pollutant, known to cause lung injury and altered function. Using established models of acute (0.8 ppm, 3 h) and episodic (1.5 ppm, 2 h, 2 times/wk, 6 wk) inhalation exposure, we observed distinct structural changes in the lung; whereas acutely, ozone primarily disrupts the bronchiolar epithelial barrier, episodic exposure causes airway remodeling. Herein we examined how these responses altered pulmonary function. A SCIREQ small animal ventilator was used to assess lung function; impedance was used to conditionally model resistance and elastance. Episodic, but not acute ozone exposure reduced the inherent and frequency-dependent tissue recoil (elastance) of the lung. Episodic ozone also increased central and high-frequency resistance relative to air control after methacholine challenge, indicating airway hyperresponsiveness. Pressure-volume (PV) loops showed that episodic ozone increased maximum lung volume, while acute ozone decreased lung volume. Episodic ozone-induced functional changes were accompanied by increases in alveolar circularization; conversely, minimal histopathology was observed after acute exposure. However, acute ozone exposure caused increases in total phospholipids, total surfactant protein D (SP-D), and low molecular weight SP-D in bronchoalveolar lavage fluid. Episodic ozone exposure only increased total SP-D. These findings demonstrate that acute and episodic ozone exposure cause distinct alterations in surfactant composition and pulmonary function. Whereas loss in PV loop area following acute ozone exposure is likely driven by increases in SP-D and inflammation, emphysematous pathology and airway hyperresponsiveness after episodic ozone appears to be the result of alterations in lung structure.

Pulmonary Surfactant in Health and Disease: An Overview

Surfactant is a complex mixture of phospholipids, mainly dipalmitoylphosphatidylcholine (DPCC) and surfactant proteins (SP); SP-A, SP-B, SP-C, and SP-D. DPCC plays a crucial role in lowering the surface tension, while SPs provide immunity against invading pathogens. SPs also enhance the activity of phospholipids, aiding in the adsorption and spread of surfactants all over the alveolar surface. Surfactant production starts as early as 24 weeks of gestation in humans and peaks at about 36-38 weeks. The generation and secretion of lung surfactants are tightly regulated processes. Surfactant is synthesized by type II alveolar cells and stored in lamellar bodies. Following stimulation, these lamellar bodies combine with the cell membrane and release their content into the alveolar spaces. Respiratory distress syndrome (RDS) is a fatal disease that primarily occurs in premature infants, and is mainly caused by the absence or dysfunction of pulmonary surfactant. The alveoli collapse due to surfactant insufficiency impairs the gas exchange in RDS causing respiratory failure. One of the treatment options for RDS in preterm infants is surfactant replacement therapy (SRT), where exogenous surfactant preparations are given to replete the levels of surfactant in the lungs. Prophylactic corticosteroids given at about 24 to 34 weeks of gestation to the pregnant mother may prevent surfactant deficiency in babies as it hastens surfactant production. In this review, we have explored the role of surfactants in the normal functioning of the lungs and different disease conditions.

Unveiling surfactant protein-A dynamics in human fetal lung development: histological and immunohistochemical insights from Myanmar.

Surfactant protein-A (SP-A) is the most prevalent protein in the pulmonary surfactant system and it is expressed in Type II alveolar epithelial cells. We evaluated SP-A expression in 92 fetal human lungs at various gestational ages in Myanmar (Burma) using hematoxylin and eosin staining and immunohistochemical assays. We detected tubular structures in the fetal lungs during the canalicular stage of development at gestational weeks 22-25. Bronchioles were detected between 26-27 and 28-33 weeks, when primitive alveoli were evident. At 34-40 weeks, clusters of alveolar sacs opened from the alveolar ducts during the saccular development stage. At 40-44 weeks, extremely thin alveolar walls resembled sections of adult lungs. Type II cells secreting surfactant were undetectable at 22-25 weeks, but became detectable from 26 weeks, and the abundance of Type II cells increased after 28 weeks. Surfactant spread throughout the alveoli at 34 weeks. Because the positivity index of these cells significantly correlated with a gestational age of 26-33 weeks, we established a formula to estimate gestational age. Our findings improve understanding of fetal lung development and maturity, and provide valuable insights into the diagnosis and management of respiratory disorders among premature infants in Myanmar.

Surfactant Protein-A and its immunomodulatory roles in infant respiratory syncytial virus infection: a potential for therapeutic intervention?

The vast majority of early-life hospital admissions globally highlight respiratory syncytial virus (RSV), the leading cause of neonatal lower respiratory tract infections, as the major culprit behind the poor neonatal outcomes following respiratory infections. Unlike those of older children and adults, the immune system of neonates looks rather unique, therefore mostly counting on the innate immune system and antibodies of maternal origins. The collaborations between cells and immune compartments during infancy inclines bias toward a T-helper 2 (Th2) immune profile and thereby away from a T-helper 1 (Th1) immune response. What makes it more problematic is that RSV infection also tends to elicit a stronger Th2-biased immune response and drive an aberrant allergy-like inflammation. It is thus evident how RSV infections potentially pave the way for wheezing recurrences and childhood asthma later in life. Surfactant, the essential lung substance for normal breathing processes in mammals, has immunomodulatory properties including lung collectins such as Surfactant Protein-A (SP-A), which is the most abundant protein component of surfactant, and also Surfactant Protein-D (SP-D). Deficiency of SP-A and SP-D has been found to be associated with impaired pathogen clearance and exacerbated immune responses during infections. We therefore conducted a review of the literature to describe pathomechanisms of RSV infections during blunted neonatal immunity potentially facilitating allergy-like inflammatory events within the developing lungs and highlight the potential protective role of the humoral collectin SP-A to mitigate these in the "early in life" pulmonary immune system.

Chamomile flowers extract protects against thinner inhalation-induced lung toxicity via attenuating cytochrome P2E1 activity, surfactant deficiency, and alveolar structural injury in rats

BackgroundLungs are adversely affected by repeated exposure to thinner fumes. This study aimed to examine the pulmonary toxic effects of chronic thinner inhalation and the possible protection by chamomile administration. Adult male Wistar rats were exposed to thinner fumes for 8 weeks (4 h/day, 6 days/week), while chamomile flower extract (400 mg/kg body weight) was given orally during thinner exposure for the same period.ResultsThe study showed lung damage following chronic thinner exposure through increased cytochrome P2E1 (CYP2E1), superoxide anion (O2•−), hydrogen peroxide (H2O2), and malondialdehyde (MDA), with decreased antioxidant enzymes; superoxide dismutase (SOD), and catalase (CAT). Moreover, an elevation of lung enzymes; alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) with depletion in total protein and albumin contents in serum and bronchoalveolar lavage fluid were observed. Thinner exposure also exhibited increased lung deoxyribonucleic acid (DNA) damage, transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1), hydroxyproline (HYP), and collagen type 1 (COL-1), with decreased serum surfactant protein-A (SP-A), total and differential leukocytes (WBCs) count, except for neutrophils. Histological investigations revealed deteriorative changes along with accumulated collagen fibers affecting the lung and other respiratory organs.ConclusionSupplementation of chamomile extract succeeded in preventing thinner-induced lung oxidative stress, enzyme leakage, surfactant deficiency, DNA damage, fibrosis, and histological injury. Therefore, consumption of chamomile extract could be recommended for alleviating thinner-induced health hazards and lung toxicity.

Analysis of association of SP-C gene polymorphisms with Neonatal respiratory distress syndrome

To analyze the association between pulmonary surfactant protein C (SP-C) gene polymorphisms and the risk of Neonatal respiratory distress syndrome (NRDS). Clinical data from 168 neonates diagnosed with NRDS (NRDS group) admitted between August 2020 and June 2023 were collected. Additionally, 168 neonates without respiratory distress, born during the same period, were included as the control group. Peripheral venous blood samples (2 mL each) were collected from both groups. PCR-restriction fragment length polymorphism technique was employed to detect the polymorphisms at the SP-C gene loci p.Thr138Asn (rs4715) and p.Ser186Asn (rs1124). Hardy-Weinberg equilibrium tests were conducted for genotyping, and genotypic and allelic frequencies were compared. The association between SP-C gene polymorphisms and NRDS risk was evaluated. Furthermore, genotypic and allelic frequencies at the rs4715 and rs1124 loci were compared among NRDS cases with varying degrees of disease severity. The study was approved by the Medical Ethics Committee of Shangqiu First People's Hospital (Ethics No. 2020-031). The frequency of the variant allele (A) at the rs4715 locus was significantly higher in the NRDS group compared to the control group (32.14% vs. 24.11%, P = 0.001). The frequency of the variant genotype (AA + AC) was also higher in the NRDS group (47.02% vs. 39.29%, P = 0.043). The frequency of the variant allele (A) at the rs1124 locus was higher in the NRDS group compared to the control group (34.23% vs. 23.51%, P = 0.027), with a higher frequency of the variant genotype (AA + AG) in the NRDS group (49.40% vs. 39.29%, P = 0.019). No significant correlation was observed between the rs4715 polymorphism and the severity of NRDS (P > 0.05). Among NRDS children with grade III severity, the frequency of the variant allele (A) at the rs1124 locus was higher than in grade I and grade II children (47.62% vs. 29.22%, P = 0.020). The frequency of the variant genotype (AA + AG) was also higher in grade III children (64.28% vs. 43.84%, P = 0.040). SP-C gene polymorphisms are associated with the susceptibility to NRDS. Neonates carrying the AA genotype and the A allele at the rs1124 locus are at a higher risk of severe NRDS. These findings have provided further evidence for early screening, diagnosis, and treatment of NRDS.

Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles

IntroductionAlveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular...

Induction of Early Pulmonary Senescence in Experimental Sepsis.

Background: Sepsis continues to pose a significant threat to human life and represents a substantial financial burden. In addition to replicative stress resulting from telomeric loss, recent studies have identified multiple factors contributing to cell cycle arrest. Furthermore, our understanding of pathways associated with cellular senescence, such as CD47-mediated suppression of efferocytosis, has expanded. However, beyond in vitro experiments, the impact of cell stress during complex systemic illnesses, including sepsis, remains poorly understood. Consequently, we conducted an investigation into molecular alterations related to senescence-associated pulmonary mechanisms during experimental non-pulmonary sepsis.Methods: Male C57BL/6JRj mice were anesthetized and subjected to either control conditions (sham) or cecal ligation and puncture (CLP) to induce sepsis. 24 h or 7 d after CLP, animals were sacrificed and blood, bronchoalveolar fluids and lungs were harvested and analyzed for morphological and biochemical changes.Results: Histological damage in pulmonary tissue, as well as increases in plasma levels of surfactant protein D, indicated development of alveolar-focused acute lung injury after CLP. Additionally, we observed a significant upregulation of the CD47-QPCTL-SHP-1-axis in lungs of septic mice. Whereas the expression of p16, a marker primarily indicating manifested forms of senescence, was decreased after CLP, the early marker of cellular senescence, p21, was increased in the lungs during sepsis. Later, at 7 d after CLP, pulmonary expression of CD47 and QPCTL-1 was decreased, whereas SHP-1 was significantly enhanced.Conclusion: Our findings suggest an activation of senescent-associated pathways during experimental sepsis. However, expanding the experiments to other organ systems and in vivo long-term models are necessary to further evaluate the sustained mechanisms and immunopathophysiological consequences of cellular senescence triggered by septic organ injury.

Yes-associated protein is dysregulated in human congenital diaphragmatic hernia patients during mid and end gestation.

Yes-associated protein (YAP) is implicated in congenital diaphragmatic hernia (CDH). This study aims to investigate the abundance of YAP and its inactive form, phosphorylated YAP (p-YAP), in fetal human lung tissues from CDH cases compared to control cases at mid-gestation and end-gestation. Immunofluorescence was performed to assess the abundance of YAP and p-YAP in lung tissues from human CDH and control fetuses who died from causes other than CDH. Additionally, the impact on cellular differentiation was evaluated by assessing the expression of Homeodomain-only protein X (HOPX) and Surfactant protein C (SPC). Immunostaining revealed a higher abundance of YAP and p-YAP in both mid-gestation and end-gestation lung tissues. Notably, the abundance of p-YAP was increased in CDH tissues compared to controls, indicating higher levels of the inactive form of YAP in CDH. HOPX and SPC staining showed CDH tissues had a higher number of SPC-positive cells and fewer HOPX-positive cells at end-gestation. Our findings suggest that in CDH, YAP is predominantly present in its inactive form, p-YAP, potentially disrupting normal lung development and differentiation. This underscores the potential involvement of YAP dysregulation in the pathogenesis of CDH.

ErbB deletion effect on pulmonary intracellular surfactant distribution

Background: Alveolar epithelial type II cells (AEII) synthesize, store, and recycle surfactant. Lipids and primarily hydrophobic surfactant proteins (SPs) are stored in lamellar bodies (Lbs) while the hydrophilic SPs and the precursors of hydrophobic SPs are stored in multivesicular bodies (mvb). ErbB4-receptor and its ligand neuregulin (NRG) are important regulators of fetal lung development and fetal surfactant synthesis. ErbB4 deletion leads predominantly to an alveolar simplification. We hypothesized that ErbB4 deletion affects the ultrastructure of AEII, specifically Lb and the intracellular distribution of the immunomodulating hydrophilic SP-A and the hydrophobic SP-B. Material and Methods: Using a HER4 transgenic cardiac rescue mouse model, AEII were characterized stereologically in lungs of juvenile transgenic HER4heart+/− and HER4heart−/− mice. The ultrastructure of Lb and the intracellular distribution of SPs were evaluated by immune electron microscopy. A preferential nonrandom labeling of a compartment for SP is present, if the relative labeling index (RLI) > 1and the chi-quadrat test is significant. Results: HER4 deletion had no significant effects on size of AEII and volume fractions of subcellular organelles as well as on the volume weighted mean volume of Lb in HER4heart−/− when compared to HER4heart+/− mice. The cytoplasm was preferentially labeled for SP-A in the AEII of both genotypes. Lbs were preferential labeled for SP-A in the AEII of HER4heart−/−, but not in the AEII of HER4heart+/− mice. SP-B was preferentially distributed over Lbs in AEII independent of the genotype, however, the evaluated RLI was significantly higher in HER4heart−/− mice. Conclusion: HER4 deletion does not affect the ultrastructure of AEII and influence the distribution of SP-A and SP-B only moderately. Responsible for this could be compensatory mechanisms caused by the redundancy of ErbB receptors.

Moving on from clinical animal-derived surfactants to peptide-based synthetic pulmonary surfactant.

Research on lung surfactant has exerted a great impact on newborn respiratory care and significantly improved survival and outcome of preterm infants with respiratory distress syndrome (RDS) due to surfactant deficiency because of lung immaturity. Current clinical, animal-derived, surfactants are among the most widely tested compounds in neonatology However, limited availability, high production costs, and ethical concerns about using animal-derived products constitute important limitations in their universal application. Synthetic lung surfactant offers a promising alternative to animal-derived surfactant by providing improved consistency, quality and purity, availability and scalability, ease of production and lower costs, acceptance, and safety for the treatment of neonatal RDS and other lung conditions. Third-generation synthetic surfactants built around surfactant protein B (SP-B) and C (SP-C) peptide mimics stand at the forefront of innovation in neonatal pulmonary medicine, while nasal continuous positive airway pressure (nCPAP) has become the standard non-invasive respiratory support for preterm infants. nCPAP can prevent the risk of chronic lung disease (bronchopulmonary dysplasia) and reduce lung injury by avoiding intubation and mechanical ventilation, is a relatively simple technique and can be initiated safely and effectively in the delivery room. Combining nCPAP with noninvasive, preferably aerosol, delivery of synthetic lung surfactant promises to improve respiratory outcomes for preterm infants, especially in low-and-middle income countries.

Update prognostic potency of surfactant protein D (SP-D) in the COVID-19 landscape: an In-depth meta-analytical exploration.

Surfactant Protein D (SP-D), a key component of the innate immune system, has attracted significant interest for its potential role in the pathophysiology and prognosis of COVID-19. This systematic review and meta-analysis aim to clarify the prognostic importance of SP-D levels in COVID-19 patients. A comprehensive literature search was conducted using PubMed, Web of Science, Cochrane Library, Scopus, EMBASE, and Google Scholar, covering studies published from January 2000 to January 2024. The inclusion criteria focused on studies measuring SP-D levels in the serum or plasma of COVID-19 patients, comparing severe and non-severe cases. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model to assess overall effect sizes. Meta-regressions and subgroup analyses were performed to identify potential sources of heterogeneity, including patient age, assay techniques, and gender ratio. The meta-analysis incorporated data from nine studies involving 5,410 COVID-19 patients. Elevated SP-D levels were significantly correlated with increased disease severity, yielding an SMD of 0.642 (95% CI: 0.314 to 0.870; p = 0.012). This meta-analysis confirms the prognostic significance of SP-D in the context of COVID-19. Elevated SP-D levels are associated with severe disease outcomes, highlighting its potential as a prognostic biomarker.

Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study.

This study aimed to determine the clinical significance of Krebs von den Lungen-6 (KL-6), surfactant proteins A (SP-A) and D (SP-D) in the evaluation and management of interstitial lung disease (ILD). Serum KL-6, SP-A, SP-D levels were measured in122 unique consecutive patients referred for connective tissue disease (CTD) associated ILD (CTD-ILD) autoantibodies and 120"healthy" controls. Patients' charts were retrospectively reviewed and categorized as ILD and non-ILD or CTD-ILD and other ILD. All biomarkers were evaluated for diagnosis and moderate vs. severe ILD based on high-resolution computed tomography (HRCT). ILD was diagnosed in 52 % (n=64) and non-ILD in 48 % (n=58). ILD patients were categorized as other ILD (61 %, n=39) or CTD-ILD (39 %, n=25). Patients with ILD had significantly elevated levels of SP-A (p<0.02), KL-6 or SP-D (both p<0.0001) when compared to those with non-ILD. The mean levels of all biomarkers were significantly elevated levels in the ILD compared to non-ILD group (p<0.0001). No significant difference in biomarker levels between CTD-ILD and other ILD groups (p≥0.900). Biomarkers had comparable specificities (89-93 %) however; sensitivities were variable at 75 , 77 and 17 % for KL-6, SP-D and SP-A, respectively. Combination of KL-6 and SP-D yielded comparable diagnostic accuracy to all biomarkers with median levels significantly higher in patients with severe vs. mild disease. KL-6 and SP-D levels are elevated in ILD and therefore contribute to the diagnosis and risk stratification for patient management.

Genetic Risk Factors in Idiopathic and Non-Idiopathic Interstitial Lung Disease: Similarities and Differences.

Recent advances in genetics and epigenetics have provided critical insights into the pathogenesis of both idiopathic and non-idiopathic interstitial lung diseases (ILDs). Mutations in telomere-related genes and surfactant proteins have been linked to familial pulmonary fibrosis, while variants in MUC5B and TOLLIP increase the risk of ILD, including idiopathic pulmonary fibrosis and rheumatoid arthritis-associated ILD. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs such as miR-21 and miR-29, regulate fibrotic pathways, influencing disease onset and progression. Although no standardized genetic panel for ILD exists, understanding the interplay of genetic mutations and epigenetic alterations could aid in the development of personalized therapeutic approaches. This review highlights the genetic and epigenetic factors driving ILD, emphasizing their potential for refining diagnosis and treatment.

Exploration of the hierarchical assembly space of collagen-like peptides beyond the triple helix

The de novo design of self-assembling peptides has garnered significant attention in scientific research. While alpha-helical assemblies have been extensively studied, exploration of polyproline type II helices, such as those found in collagen, remains relatively limited. In this study, we focus on understanding the sequence-structure relationship in hierarchical assemblies of collagen-like peptides, using defense collagen Surfactant Protein A as a model. By dissecting the sequence derived from Surfactant Protein A and synthesizing short collagen-like peptides, we successfully construct a discrete bundle of hollow triple helices. Amino acid substitution studies pinpoint hydrophobic and charged residues that are critical for oligomer formation. These insights guide the de novo design of collagen-like peptides, resulting in the formation of diverse quaternary structures, including discrete and heterogenous bundled oligomers, two-dimensional nanosheets, and pH-responsive nanoribbons. Our study represents a significant advancement in the understanding and harnessing of collagen higher-order assemblies beyond the triple helix.

Impact of vitamin D on hyperoxic acute lung injury in neonatal mice

BackgroundProlonged exposure to hyperoxia can lead to hyperoxic acute lung injury (HALI) in preterm neonates. Vitamin D (VitD) stimulates lung maturation and acts as an anti-inflammatory agent. Our objective was to determine if VitD provides a dose-dependent protective effect against HALI by reducing inflammatory cytokine expression and improving alveolarization and lung function in neonatal mice.MethodsC57BL/6 mouse neonates were randomized and placed in room air or hyperoxic (85% O2) conditions for 6 days. Control, low (5 ng/neonate) and high (25 ng/neonate) doses of VitD were administered daily beginning at day 2 via oral gavage. Lung tissue was analyzed for edema, changes in pulmonary structure and function, and inflammatory cytokine expression.ResultsNeonatal mice treated with VitD in hyperoxic conditions had improved weight gain, reduced pulmonary edema and increased alveolar surface area compared to untreated pups in hyperoxia. No significant changes in cytokine expression were observed between untreated and VitD neonates. While changes in surfactant protein mRNA expression were impacted by hyperoxia and VitD administration, no significant changes in alveolar type II cell percentages were observed. At 3 weeks, mice in hyperoxia treated with VitD had greater lung compliance, diminished airway reactivity and improved weight gain.ConclusionsHigh dose VitD significantly limited harmful effects of HALI. These results suggest that supplementation of VitD to neonatal mice during hyperoxia exposure provides both short-term and long-term protective benefits against HALI.