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Numerous studies have been conducted to investigate the impact of microplastics on soil eco-system, yet little attention has been given to the specific effects of mulch microplastics and the leaching of plastic additives from mulch films. This review inspects the propensity of commonly used plastic additives in mulch films, such as Di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), and benzophenones (BPs), to migrate into soils and pose potential risks to soil biota. Further, we highlight the degradation of non-biodegradable plastic mulch films over time, which leads to an increase in the release of plastic additives and microplastics into agricultural soils. DEHP has been detected in high concentrations for example 25.2 mg/kg in agricultural soils, indicating a potential risk of uptake, translocation and accumulation in plants, ultimately altering soil physicochemical properties and affecting soil microflora and invertebrates. The review also explores how exposure to ultraviolet (UV) radiation and microbial activities accelerates the weathering of mulch films. Moreover, the resultant plastic additives and mulch microplastics can lead to genotoxicity and growth inhibition in earthworms (Eisenia fetida) and negatively impact the soil microbiome. Despite the significant implications, there has been a lack of comprehensive reviews comparing the effects of non-biodegradable mulch film additives on agricultural soil flora and fauna. Therefore, this review addresses the knowledge gaps providing a bibliometric analysis and eco-toxicological evaluation, discussing the challenges and future perspectives regarding mulch plastic additives and microplastics, thus offering a comprehensive understanding of their impact., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Plasticizers, essential additives for enhancing plastic properties, have emerged as significant environmental and health concerns due to their persistence and widespread use. This study provides an in-depth exploration of plasticizers, focusing on their types, structures, properties, production methods, environmental distribution, and associated risks. The findings reveal that petroleum-based phthalates, particularly di-(2-ethylhexyl) phthalate (DEHP), are prevalent in aquatic and terrestrial environments, primarily due to the gradual degradation of plastic polymers. In the analysis of 39 studies on water contamination during the period of 2022-2023, only 22 works could be extracted due to insufficient details on the numerical value of plasticizer concentrations. Similarly, soil and sediment contamination studies were fewer, with only 11 studies focusing on sediments. These studies reveal that high plasticizer concentrations, notably in industrial and urban areas, often exceed recommended environmental limits, posing risks to ecological integrity and human health through bioaccumulation. Bioaccumulation of these compounds in soil and water could negatively affect the microbial communities, nutrient cycling, and could destabilize the overall ecological integrity. Concerns about their direct uptake by plants and potential risks to human health and food safety are highlighted in this study due to the high concentrations exceeding the threshold values. The review evaluates current treatment technologies, including metal-organic frameworks, electrochemical systems, multi-walled carbon nanotubes, and microbial degradation, noting their potential and challenges related to cost and energy consumption. It underscores the need for improved detection protocols, cost-effective treatments, stricter regulations, public awareness, and collaborative research to mitigate the adverse impacts of plasticizers on ecosystems and human health.

Rationale: Cortactin, an actin-binding cytoskeletal protein, plays a crucial role in maintaining endothelial cell (EC) barrier integrity and regulating vascular permeability. The gene encoding cortactin, CTTN, is implicated in various lung inflammatory disorders. Despite this, the transcriptional regulation of CTTN by inflammatory stimuli and promoter SNPs remains unexplored., Methods: We transfected human lung ECs with a full-length CTTN promoters linked to a luciferase reporter to measure promoter activity. SNP-containing CTTN promoter was created via site-directed mutagenesis. Transfected ECs were exposed to LPS (PAMP), TNF-α (cytokine), cyclic stretch (CS), FG-4592 (HIF-inducer), NRF2 (anti-oxidant modulator), FTY-(S)-phosphate (endothelial barrier enhancer), and 5'-Aza (demethylation inducer). Immunohistochemistry was used to assess cortactin expression in mouse lungs exposed to LPS., Results: LPS, TNF-α, and 18%CS significantly increased CTTN promoter activities in a time-dependent manner (P<0.05). The variant rs34612166 (-212T/C) markedly enhanced LPS- and 18%CS- induced CTTN promoter activities (P<0.05). FG-4592 significantly boosted CTTN promoter activities (P<0.01), which were partially inhibited by HIF1α (KC7F2) and HIF2α (PT2385) inhibitors (P<0.05). NRF2 activator Bixin increased CTTN promoter activities, whereas NRF2 inhibitor Brusatol reduced them (P<0.05). 5'-Aza increased CTTN promoter activities by 2.9-fold (P<0.05). NF-κB response element mutations significantly reduced CTTN promoter activities response to LPS and TNFα. FTY-(S)-phosphate significantly increased CTTN promoter activities in 24 h. In vivo, cortactin levels were significantly elevated in inflammatory mouse lungs exposed to LPS for 18 h., Conclusion: CTTN transcriptional is significantly influenced by inflammatory factors and promoter variants. Cortactin, essential in mitigating inflammatory edema, presents a promising therapeutic target to alleviate severe inflammatory disorders., (© 2024 The Author(s).)

Rationale: Circadian systems drive the expression of multiple genes in nearly all cells and coordinate cellular-, tissue-, and system-level processes that are critical to innate immunity regulation., Objective: We examined the effects of circadian rhythm disorganization, produced by light shift exposure, on innate immunity-mediated inflammatory lung responses including vascular permeability and gene expression in a C57BL/6J murine model of inflammatory lung injury., Methods: A total of 32 C57BL/6J mice were assigned to circadian phase shifting (CPS) with intratracheal phosphate-buffered saline (PBS), CPS with intratracheal lipopolysaccharide (LPS), control (normal lighting) condition with intratracheal PBS, and control condition with intratracheal LPS. Bronchoalveolar lavage (BAL) protein, cell counts, tissue immunostaining, and differentially expressed genes (DEGs) were measured in lung tissues at 2 and 10 weeks., Measurements and Results: In mice exposed to both CPS and intratracheal LPS, both BAL protein and cell counts were increased at both 2 and 10 weeks compared to mice exposed to LPS alone. Multiple DEGs were identified in CPS-LPS-exposed lung tissues compared to LPS alone and were involved in transcriptional pathways associated with circadian rhythm disruption, regulation of lung permeability, inflammation with Rap1 signaling, and regulation of actin cytoskeleton. The most dysregulated pathways included myosin light chain kinase, MAP kinase, profilin 2, fibroblast growth factor receptor, integrin b4, and p21-activated kinase., Conclusion: Circadian rhythm disruption results in exacerbated immune response and dysregulated expression of cytoskeletal genes involved in the regulation of epithelial and vascular barrier integrity-the mechanistic underpinnings of acute lung injury. Further studies need to explore circadian disorganization as a druggable target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Casanova, De Armond, Sammani, Sun, Sun, Kempf, Bime, Garcia and Parthasarathy.)

Objective: Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure., Methods: Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized., Results: Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα)., Conclusion: The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality., Competing Interests: COI Disclosures: Joe GN Garcia MD is CEO and Founder of Aqualung Therapeutics Corporation. All other authors report no conflict of interest.

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis. We investigated humanized ALT-100 and ALT-300 mAb with high eNAMPT-neutralizing capacity in an infarct rat model to test our hypothesis. ALT-300 was 99m Tc-labeled to generate 99m Tc-ALT-300 for imaging myocardial eNAMPT expression at 2 hours, 1 week, and 4 weeks post-IRI. The eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg) or saline was administered intraperitoneally at 1 hour and 24 hours post-reperfusion and twice a week for 4 weeks. Cardiac function changes were determined by echocardiography at 3 days and 4 weeks post-IRI. 99m Tc-ALT-300 uptake was initially localized to the ischemic area at risk (IAR) of the left ventricle (LV) and subsequently extended to adjacent non-ischemic areas 2 hours to 4 weeks post-IRI. Radioactive uptake (%ID/g) of 99m Tc-ALT-300 in the IAR increased from 1 week to 4 weeks (0.54 ± 0.16 vs. 0.78 ± 0.13, P < 0.01). Rats receiving ALT-100 mAb exhibited significantly improved myocardial histopathology and cardiac function at 4 weeks, with a significant reduction in the collagen volume fraction (%LV) compared to controls (21.5 ± 6.1% vs. 29.5 ± 9.9%, P < 0.05). Neutralization of the eNAMPT/TLR4 inflammatory cascade is a promising therapeutic strategy for MI by reducing chronic inflammation, fibrosis, and preserving cardiac function., Competing Interests: Declaration of Competing Interest Dr. Joe G.N. Garcia is CEO and Founder of Aqualung Therapeutics Corporation. All other authors report no conflict of interest or relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The objectives of this study were to assess the role of soil organic matter on retaining plastic additives, Di(2-ethylhexyl) phthalate (DEHP), Bisphenol A (BPA) and Benzophenone (BP), to postulate the retention mechanisms and mobility in soil. Batch experiments were conducted for red yellow podzolic soil (OM) and soil subjected to high temperature oxidation at 600 °C for 2 h to remove total organic matter (OMR). Pristine soil, which contains organic matter abbreviated as OM (soil with organic matter) whereas total organic matter removed soil is abbreviated as OMR (organic matter removed soil). The pH edge and kinetic experiments were conducted with 20 g/L soil suspension spiked with 10 mg/L of each additive, whereas 1-20 mg/L concentration range was used in isotherm experiments and analyzed using high performance liquid chromatography. DEHP demonstrated the highest retention, 331 and 615.16 mg/kg in OM and OMR soils respectively, at pH 6.6. However, BPA and BP showed highest retentions of 132 and 128 mg/kg, respectively around pH 4.3 in pristine soil. DEHP interaction with soil OM indicated weak physical bonding whereas chemisorption to OMR soil. In the case of BPA, physisorption governed its interaction with both soil organic matter and mineral fraction. Nevertheless, BP demonstrated chemical interactions with OM and minerals. Desorption of DEHP was close to 100% however, BPA and BP were <15%. Overall, DEHP and BPA could be easily released into soil water and possibly be available for plant uptake while, BP is immobilized in soil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sammani Ramanayaka reports financial support was provided by Lancaster University, United Kingdom., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1-14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes. Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates., Competing Interests: JG MD is CEO and founder of Aqualung Therapeutics Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmed, Casanova, Zaghloul, Gupta, Rodriguez, Robbins, Kempf, Sun, Song, Hernon, Sammani, Camp, Moreira, Hsu and Garcia.)

Introduction: Intravenous oxygen therapeutics present an appealing option for improving arterial oxygenation in patients with acute hypoxemic respiratory failure, while limiting iatrogenic injury from conventional respiratory management., Methods: We used an established two-hit murine model of acute lung injury (ARDS/VILI) to evaluate the effect of intravenous dodecafluoropentane (DDFPe) on oxygen saturation and bronchoalveolar lavage cell counts and protein levels. Twenty hours after challenge with intratracheal lipopolysaccharide, mice were intubated and ventilated with high tidal volumes (4 h) to produce acute lung injury. DDFPe (0.6 mL/kg) or saline was administered by IV bolus injection at the initiation of mechanical ventilation and again at 2 h. Oxygen saturation was measured every 15 min. Bronchoalveolar lavage was performed at the conclusion of the experiment., Results: The two-hit ARDS/VILI model produced substantial inflammatory acute lung injury reflected by markedly increased bronchoalveolar lavage (BAL) cell counts compared to BAL cell counts in spontaneous breathing controls (5.29 ± 1.50 × 10 -6 vs 0.74 ± 0.014 × 10 -6 cells/mL) Similarly, BAL protein levels were markedly elevated in ARDS/VILI-challenged mice compared with spontaneous breathing controls (1109.27 ± 223.80 vs 129.6 ± 9.75 ng/mL). We fit a linear mixed effects model that showed a significant difference in oxygen saturation over time between DDFPe-treated mice and saline-treated mice, with separation starting after the 2-h injection. DDFPe-treated ARDS/VILI-challenged mice also exhibited significant reductions in BAL cell counts but not in BAL protein., Conclusion: DDFPe improves oxygen saturation in a murine model of ARDS/VILI injury with the potential for serving as an intravenous oxygen therapeutic., (© 2023. The Author(s).)

We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene ( SELPLG ), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)- and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS- and VILI-induced lung injury. In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPS-mediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed. These findings indicate SELPLG transcriptional regulation by clinically-relevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Rationale: Effective therapies to reduce the severity and high mortality of pulmonary vasculitis and diffuse alveolar hemorrhage (DAH) in patients with systemic lupus erythematosus (SLE) is a serious unmet need. We explored whether biologic neutralization of eNAMPT (extracellular nicotinamide phosphoribosyl-transferase), a novel DAMP and Toll-like receptor 4 ligand, represents a viable therapeutic strategy in lupus vasculitis., Methods: Serum was collected from SLE subjects (n = 37) for eNAMPT protein measurements. In the preclinical pristane-induced murine model of lung vasculitis/hemorrhage, C57BL/6 J mice (n = 5-10/group) were treated with PBS, IgG (1 mg/kg), or the eNAMPT-neutralizing ALT-100 mAb (1 mg/kg, IP or subcutaneously (SQ). Lung injury evaluation (Day 10) included histology/immuno-histochemistry, BAL protein/cellularity, tissue biochemistry, RNA sequencing, and plasma biomarker assessment., Results: SLE subjects showed highly significant increases in blood NAMPT mRNA expression and eNAMPT protein levels compared to healthy controls. Preclinical pristane-exposed mice studies showed significantly increased NAMPT lung tissue expression and increased plasma eNAMPT levels accompanied by marked increases in alveolar hemorrhage and lung inflammation (BAL protein, PMNs, activated monocytes). In contrast, ALT-100 mAb-treated mice showed significant attenuation of inflammatory lung injury, alveolar hemorrhage, BAL protein, tissue leukocytes, and plasma inflammatory cytokines (eNAMPT, IL-6, IL-8). Lung RNA sequencing showed pristane-induced activation of inflammatory genes/pathways including NFkB, cytokine/chemokine, IL-1β, and MMP signaling pathways, each rectified in ALT-100 mAb-treated mice., Conclusions: These findings highlight the role of eNAMPT/TLR4-mediated inflammatory signaling in the pathobiology of SLE pulmonary vasculitis and alveolar hemorrhage. Biologic neutralization of this novel DAMP appears to serve as a viable strategy to reduce the severity of SLE lung vasculitis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joe G.N. Garcia, MD reports financial support and equipment, drugs, or supplies were provided by Aqualung Therapeutics, LLC. Joe G.N. Garcia, MD reports a relationship with Aqualung Therapeutics, LLC that includes: equity or stocks. Joe G.N. Garcia, MD has patent pending to Aqualung Therapeutics, LLC., (© 2022 Published by Elsevier B.V.)

The loss of vascular integrity is a cardinal feature of acute inflammatory responses evoked by activation of the TLR4 inflammatory cascade. Utilizing in vitro and in vivo models of inflammatory lung injury, we explored TLR4-mediated dysregulated signaling that results in the loss of endothelial cell (EC) barrier integrity and vascular permeability, focusing on Dock1 and Elmo1 complexes that are intimately involved in regulation of Rac1 GTPase activity, a well recognized modulator of vascular integrity. Marked reductions in Dock1 and Elmo1 expression was observed in lung tissues (porcine, rat, mouse) exposed to TLR4 ligand-mediated acute inflammatory lung injury (LPS, eNAMPT) in combination with injurious mechanical ventilation. Lung tissue levels of Dock1 and Elmo1 were preserved in animals receiving an eNAMPT-neutralizing mAb in conjunction with highly significant decreases in alveolar edema and lung injury severity, consistent with Dock1/Elmo1 as pathologic TLR4 targets directly involved in inflammation-mediated loss of vascular barrier integrity. In vitro studies determined that pharmacologic inhibition of Dock1-mediated activation of Rac1 (TBOPP) significantly exacerbated TLR4 agonist-induced EC barrier dysfunction (LPS, eNAMPT) and attenuated increases in EC barrier integrity elicited by barrier-enhancing ligands of the S1P1 receptor (sphingosine-1-phosphate, Tysiponate). The EC barrier-disrupting influence of Dock1 inhibition on S1PR1 barrier regulation occurred in concert with: 1) suppressed formation of EC barrier-enhancing lamellipodia, 2) altered nmMLCK-mediated MLC2 phosphorylation, and 3) upregulation of NOX4 expression and increased ROS. These studies indicate that Dock1 is essential for maintaining EC junctional integrity and is a critical target in TLR4-mediated inflammatory lung injury., Competing Interests: Declaration of competing interest Joe GN Garcia, MD is CEO and founder of Aqualung Therapeutics Corporation. All other authors declare no competing financial interests., (Copyright © 2022. Published by Elsevier B.V.)

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system., Methods: HA of 10 kDa molecular weight (HA10) was radiolabeled with 125 I and 99m Tc respectively to produce [ 125 I]I-HA10 and [ 99m Tc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [ 99m Tc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS., Results: [ 99m Tc]Tc-HA10 and [ 125 I]I-HA10 had similar biodistribution and localization at inflammatory sites. [ 99m Tc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [ 99m Tc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [ 99m Tc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining., Conclusions: [ 99m Tc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [ 99m Tc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS., (Copyright © 2022. Published by Elsevier Inc.)

Background: Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes., Methods: Plasma biomarker levels and biomarker protein expression in lung and lymph nodes tissues (immunohistochemical studies) from sarcoidosis subjects with limited disease and progressive (complicated) sarcoidosis were performed. Gene expression of the protein-coding genes included in this panel was analyzed using RNAseq in sarcoidosis granulomatous tissues from lung and lymph nodes., Results: Except for IL-8, plasma levels of each biomarker-eNAMPT, IL-1RA, IL-6, ANG-2, and HBEGF-were significantly elevated in sarcoidosis subjects compared to controls. In addition, plasma levels of HBEGF were elevated in complicated sarcoidosis, while eNAMPT and ANG-2 were observed to serve as markers of lung fibrosis in a subgroup of complicated sarcoidosis. Genomic studies corroborated HBEGF and NAMPT among the top dysregulated genes and identified cytokine-related and fibrotic pathways in lung granulomatous tissues from sarcoidosis., Conclusion: These findings suggest HBEGF, eNAMPT, and ANG-2 may serve as potential novel indicators of the clinical severity of sarcoidosis disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Casanova, Reyes-Hernon, Gregory, Sun, Bermudez, Hufford, Oita, Camp, Hernandez-Molina, Serrano, Sun, Fimbres, Mirsaeidi, Sammani, Bime and Garcia.)

Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality., Competing Interests: Author JG was employed by the company is CEO of Aqualung Therapeutics, the company providing the ALT-100 mAb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sammani, Bermudez, Kempf, Song, Fleming, Reyes Hernon, Hufford, Tang, Cai, Camp, Natarajan, Jacobson, Dudek, Martin, Karmonik, Sun, Sun, Casanova, Bime and Garcia.)