Persistent Lung Injury Research Articles

Recent symptomatic Omicron infection reduced COVID-19 pneumonia risk during reinfection: A computed tomography–based cohort study

ObjectivesSARS-CoV-2 infection could cause persistent lung injury or indicate potential genetic susceptibilities. Although infection-elicited hybrid immunity could protect against severe COVID-19, it remains unknown whether recent infection could reduce pneumonia risk during reinfection due to insufficient viral and chest computed tomography (CT) screening. MethodsA total of 15,598 patients, 96% fully vaccinated and 52% boosted, from Xiangyang, China, who had symptomatic COVID-19 and chest CT scans during the first Omicron BF.7 wave in December 2022 to January 2023, were followed through the second Omicron XBB.1.5 wave between May and August 2023. A total of 17,968 second-wave patients with COVID-19 with chest CT scans but without previous symptomatic COVID-19 were enrolled as first-time infection controls. ResultsA total of 19.6% (3,061 of 15,598) first-wave patients were diagnosed with pneumonia. Among second-wave reinfected patients, only 0.2% (four of 2202) developed pneumonia, which was lower than the 1.7% (311 of 17,968) pneumonia prevalence among the second-wave first-time patients, with an adjusted relative risk of 0.11 (95% confidence interval: 0.04-0.29). A total of 1.3% (40 of 3,039) first-wave pneumonia survivors showed residual abnormal patterns in follow-up CT scans within 8 months after pneumonia diagnosis. ConclusionsIn a highly vaccinated population, previous symptomatic Omicron infection within 8 months reduced pneumonia risk during reinfection. Uninfected individuals might need up-to-date vaccination to reduce pneumonia risk.

Abstract 17260: Endothelium-Targeted Nanoparticle Delivery of FOXM1 Reactivates Aging-Impaired Endothelial Regeneration for Vascular Repair and Inflammatory Lung Injury Resolution: Precision Gene Therapy of Acute Respiratory Distress Syndrome

Introduction: Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). However, the underlying molecular mechanisms remain elusive and there is no effective therapy for ARDS. Hypothesis: Impaired endothelial regeneration and vascular repair in aged lungs causes persistent lung injury leading to high incidence of ARDS and high mortality in elderly patients following sepsis challenge. Methods: Genetic lineage tracing was employed to determine the cell origin of endothelial regeneration. Aged Foxm1Tg mice was used for assessing the role of FoxM1 in activating endothelial regeneration. Endothelium-targeted nanoparticles were employed to deliver FOXM1 gene selectively to endothelial cells (ECs) in aged mice. Methylation analysis was employed to determine how aging impairs FoxM1 expression. Results: Genetic lineage tracing study showed that endothelial regeneration was mediated by lung endothelial proliferation in adult mice whereas this intrinsic regenerative program was impaired in aged mice. Expression of FoxM1, an important mediator of endothelial regeneration in young adult mice, was not induced in lungs of aged mice due to aging-induced hypermethylation of the Foxm1 promoter. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of FOXM1 gene reactivated endothelial regeneration, normalized vascular repair and promoted survival of aged mice following sepsis. Furthermore, nanoparticle delivery of FoxM1 gene selectively in lung ECs also reactivated endothelial regeneration in aged mice, supporting the novel concept of precision gene therapy. In COVID-19 lung autopsy samples, FOXM1 expression was not induced in vascular ECs of elderly patients in contrast to mid-age patients, validating the clinical relevance of our findings. Conclusions: We have demonstrate that persistent lung injury and high mortality in aged mice following sepsis challenge is ascribed to impaired endothelial regeneration and vascular repair. Therapeutic reactivation of FoxM1-dependent endothelial regeneration and vascular repair represents a potential effective therapy for elderly ARDS patients by endothelium-targeted nanoparticle delivery of FOXM1 gene.

Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury.

Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury and high mortality in aged mice after sepsis challenge were attributable to impaired endothelial regeneration and vascular repair. Genetic lineage tracing study showed that endothelial regeneration after sepsis-induced vascular injury was mediated by lung resident endothelial proliferation in young adult mice, whereas this intrinsic regenerative program was impaired in aged mice. Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of the FOXM1 gene driven by an endothelial cell (EC)-specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. Mechanistically, aging-induced Foxm1 promoter hypermethylation in mice, which could be inhibited by decitabine treatment, inhibited Foxm1 induction after sepsis challenge. In COVID-19 lung autopsy samples, FOXM1 was not induced in vascular ECs of elderly patients in their 80s, in contrast with middle-aged patients (aged 50 to 60 years). Thus, reactivation of FoxM1-mediated endothelial regeneration and vascular repair may represent a potential therapy for elderly patients with ARDS.

Oxidative Stress and Lung Fibrosis: Towards an Adverse Outcome Pathway.

Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis.

Artesunate Alleviates Hyperoxia-Induced Lung Injury in Neonatal Mice by Inhibiting NLRP3 Inflammasome Activation.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in preterm infants that may cause persistent lung injury. Artesunate exhibits excellent anti-inflammatory in lung injury caused by various factors. This study aimed to investigate the effect of the artesunate on hyperoxia-induced lung injury in neonatal mice and its mechanism. A BPD model of hyperoxic lung injury in neonatal mice was established after hyperoxia (75% oxygen) exposure for 14 days, and part of the mice received intraperitoneal injections of the artesunate. H&E staining was used to observe the pathology of lung tissue, and the degree of oxidative stress in the lung tissue was determined by commercial kits. The levels of inflammatory cytokines in the serum and lung tissues of neonatal mice were detected by an enzyme-linked immunosorbent assay. Immunohistochemical experiments were performed to further evaluate the expression of IL-1β. The real-time quantitative polymerase chain reaction was used to determine the mRNA level of the NLRP3 inflammasome. The western blot assay was used to measure the levels of NLRP3 inflammasome and NF-κB pathway-related proteins. Artesunate ameliorated weight loss and lung tissue injury in neonatal mice induced by hyperoxia. The level of malondialdehyde was decreased, while the activity of superoxide dismutase and the level of glutathione increased after artesunate treatment. Artesunate reduced the level of inflammation cytokines TNF-α, IL-6, and IL-1β in the serum and lung. Moreover, artesunate inhibited the mRNA expression and protein levels of NLRP3, ASC, and caspase-1, as well as the phosphorylation of the NF-κB and IκBα. Our findings suggest that artesunate treatment can attenuate hyperoxia-induced lung injury in BPD neonatal mice by inhibiting the activation of NLRP3 inflammasome and the phosphorylation of the NF-κB pathway.

Persistent Lung Injury and Prothrombotic State in Long COVID.

Lung injury may persist during the recovery period of COVID-19 as shown through imaging, six-minute walk, and lung function tests. The pathophysiological mechanisms leading to long COVID have not been adequately explained. Our aim is to investigate the basis of pulmonary susceptibility during sequelae and the possibility that prothrombotic states may influence long-term pulmonary symptoms of COVID-19. The patient’s lungs remain vulnerable during the recovery stage due to persistent shedding of the virus, the inflammatory environment, the prothrombotic state, and injury and subsequent repair of the blood-air barrier. The transformation of inflammation to proliferation and fibrosis, hypoxia-involved vascular remodeling, vascular endothelial cell damage, phosphatidylserine-involved hypercoagulability, and continuous changes in serological markers all contribute to post-discharge lung injury. Considering the important role of microthrombus and arteriovenous thrombus in the process of pulmonary functional lesions to organic lesions, we further study the possibility that prothrombotic states, including pulmonary vascular endothelial cell activation and hypercoagulability, may affect long-term pulmonary symptoms in long COVID. Early use of combined anticoagulant and antiplatelet therapy is a promising approach to reduce the incidence of pulmonary sequelae. Essentially, early treatment can block the occurrence of thrombotic events. Because impeded pulmonary circulation causes large pressure imbalances over the alveolar membrane leading to the infiltration of plasma into the alveolar cavity, inhibition of thrombotic events can prevent pulmonary hypertension, formation of lung hyaline membranes, and lung consolidation.

Pulmonary function test and computed tomography features during follow-up after SARS, MERS and COVID-19: a systematic review and meta-analysis.

BackgroundThe COVID-19 pandemic follows severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronavirus epidemics. Some survivors of COVID-19 infection experience persistent respiratory symptoms, yet their cause and natural history remain unclear. Follow-up after SARS and MERS may provide a model for predicting the long-term pulmonary consequences of COVID-19.MethodsThis systematic review and meta-analysis aims to describe and compare the longitudinal pulmonary function test (PFT) and computed tomography (CT) features of patients recovering from SARS, MERS and COVID-19. Meta-analysis of PFT parameters (DerSimonian and Laird random-effects model) and proportion of CT features (Freeman-Tukey transformation random-effects model) were performed.FindingsPersistent reduction in the diffusing capacity for carbon monoxide following SARS and COVID-19 infection is seen at 6 months follow-up, and 12 months after MERS. Other PFT parameters recover in this time. 6 months after SARS and COVID-19, ground-glass opacity, linear opacities and reticulation persist in over 30% of patients; honeycombing and traction dilatation are reported less often. Severe/critical COVID-19 infection leads to greater CT and PFT abnormality compared to mild/moderate infection.InterpretationPersistent diffusion defects suggestive of parenchymal lung injury occur after SARS, MERS and COVID-19 infection, but improve over time. After COVID-19 infection, CT features are suggestive of persistent parenchymal lung injury, in keeping with a post-COVID-19 interstitial lung syndrome. It is yet to be determined if this is a regressive or progressive disease.

Upregulating carnitine palmitoyltransferase 1 attenuates hyperoxia-induced endothelial cell dysfunction and persistent lung injury

BackgroundBronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury.MethodsLung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or l-carnitine after hyperoxia (50% and 95% O2) followed by air recovery.ResultsWe found that incubation with l-carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with l-carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice.ConclusionsUpregulating Cpt1a by baicalin or l-carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using l-carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

Ventilatory support, such as supplemental oxygen, used to save premature infants impairs the growth of the pulmonary microvasculature and distal alveoli, leading to bronchopulmonary dysplasia (BPD). Although lung cellular composition changes with exposure to hyperoxia in neonatal mice, most human BPD survivors are weaned off oxygen within the first weeks to months of life, yet they may have persistent lung injury and pulmonary dysfunction as adults. We hypothesized that early-life hyperoxia alters the cellular landscape in later life and predicts long-term lung injury. Using single-cell RNA sequencing, we mapped lung cell subpopulations at postnatal day (pnd)7 and pnd60 in mice exposed to hyperoxia (95% O2) for 3 days as neonates. We interrogated over 10,000 cells and identified a total of 45 clusters within 32 cell states. Neonatal hyperoxia caused persistent compositional changes in later life (pnd60) in all five type II cell states with unique signatures and function. Premature infants requiring mechanical ventilation with different durations also showed similar alterations in these unique signatures of type II cell states. Pathologically, neonatal hyperoxic exposure caused alveolar simplification in adult mice. We conclude that neonatal hyperoxia alters the lung cellular landscape in later life, uncovering neonatal programing of adult lung dysfunction.

Computed tomography features predictive of intra-abdominal hypertension in acute necrotizing pancreatitis: A prospective study.

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) in acute pancreatitis (AP) are associated with development and worsening of organ failures and poor prognosis. Limited studies suggest that contrast-enhanced computed tomography(CECT) can predict the presence of IAH/ACS.We aimedto study clinical profile of patients with AP and IAH and identify predictive factors of IAH on CECT abdomen. Consecutive patients admitted with moderately severe and severe acute pancreatitis (SAP) were recruited. Clinical and radiological data were recorded prospectively. Intra-abdominal pressure was measured via a urinary catheter to document the presence of IAH/ACS. CECT abdomen was done within the first week of admission and various features that may predict the presence of IAH were studied. Thirty-seven patients (24 SAP) (mean age: 39.78 ± 13.43years and 67.6% males) with APwere studied. The most common etiology was alcohol (37.7%). IAH developed in 54.05% of patients; patients with IAH had significantly higher bedside index of severity in AP (BISAP), Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score, persistent acute lung injury (ALI), persistent acute kidney injury (AKI), persistent cardiovascular failure (CVSF), intensive care unit (ICU) stay, and mortality. Among the CT predictors, patients with IAH more commonly had moderate-gross ascites (60% vs. 23.5%, p-value - 0.026), a pancreatic necrosis of > 50% (50% vs. 17.6%, p-value - 0.04), and a round belly sign (RBS) (50% vs. 5.9%, p-value 0.03). On multivariate analysis, only RBS was predictive of IAH (odds ratio 12.6, 95% confidence interval 1.3-124.2, p-value 0.03). The sensitivity, specificity, positive predictive value, and negative predictive value for RBS were 50%, 94.12%, 90.9%, and 61.54%, respectively. Presence of RBS, moderate-gross ascites, and pancreatic necrosis of > 50% on CECT can predict the presence of IAH in these groups of patients.

Carfilzomib-Induced Pneumotoxicity in a Lung Transplant Recipient

Introduction Development of de novo donor-specific antibodies (DSA) in lung transplant (LTx) recipients is a risk factor for antibody-mediated rejection (AMR). There is no consensus on treatment protocols for patients who develop de novo DSA, but strategies include plasmapheresis (PLEX), intravenous immunoglobulin (IVIG), and carfilzomib (CFZ), a second-generation proteasome inhibitor. Dyspnea is common in patients with multiple myeloma treated with CFZ; however, lung injury in LTx recipients has not been reported. We report a case of CFZ-related pneumotoxicity in a bilateral LTx recipient undergoing treatment for possible AMR. Case Report A 71-year-old bilateral LTx recipient (October 2011) with moderate mitral regurgitation was diagnosed with probable AMR in June 2018, characterized by de novo DSA (DQ7, MFI 20,634) and FEV1 decline, but no radiographic changes or capillaritis. He was treated with PLEX, IVIG, and rituximab and had monthly PLEX/IVIG until January 2020. He tolerated the treatment well and his FEV1 stabilized. After a 5-month moratorium of PLEX/IVIG, the patient's MFI increased from 4,337 in November 2019 to 15,444 in June 2020; however, FEV1 remained stable. PLEX was resumed and CFZ was administered in August 2020, which led to a hypertensive emergency, hypoxemic respiratory failure requiring mechanical ventilation, renal failure requiring continuous renal replacement therapy, and corticosteroid therapy for persistent hypoxemia and radiographic infiltrates despite a negative fluid balance. He was extubated, his renal function recovered, and he was discharged home on supplemental oxygen and a corticosteroid taper. On outpatient follow-up, he had a 600-ml drop in FEV1, complained of severe dyspnea on exertion with hypoxemia, appeared euvolemic on physical exam, and was readmitted with evidence of ongoing lung injury. Radiographic infiltrates and hypoxemia improved with additional steroid therapy. Summary A bilateral LTx recipient presented with hypoxemic respiratory failure immediately after a 5-day course of PLEX and an infusion of CFZ. Although volume overload was a factor, persistent lung injury despite aggressive diuresis and blood pressure control suggests CFZ pneumotoxicity. Although the mechanism of CFZ lung injury is not understood, it appears to be steroid responsive, both in our patient and in other cases of proteasome inhibitor-induced pneumotoxicity.

Influenza sequelae: from immune modulation to persistent alveolitis.

Acute influenza virus infections are a global public health concern accounting for millions of illnesses worldwide ranging from mild to severe with, at time, severe complications. Once an individual is infected, the immune system is triggered in response to the pathogen. This immune response can be beneficial ultimately leading to the clearance of the viral infection and establishment of immune memory mechanisms. However, it can be detrimental by increasing susceptibility to secondary bacterial infections and resulting in permanent changes to the lung architecture, in the form of fibrotic sequelae. Here, we review influenza associated bacterial super-infection, the formation of T-cell memory, and persistent lung injury resulting from influenza infection.

Differential lung inflammation and injury with tobacco smoke exposure in Wistar Kyoto and spontaneously hypertensive rats

Objective Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and has been associated with periods of intense lung inflammation. The objective of this study was to characterize whether similar rat strains, possessing different genetic predispositions, might play a role in exacerbating the pathophysiology of COPD-like cellular and structural changes with progressive 12-week exposure to tobacco smoke (TS). Normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats were compared. Materials and methods WKY and SH rats were exposed to filtered air or to tobacco smoke at a particulate concentration of 80 mg/m3 for 4, 8, or 12 weeks. Necropsy was performed 24 h after the last exposure to obtain cells by bronchoalveolar lavage for total cell and differential counts. Scoring of lung tissues and immunohistochemical staining for M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages were performed on paraffin-embedded lung sections. Results and discussion With progressive exposure, TS-exposed SH rats demonstrated significant airspace enlargement, mucin production, and lung inflammation compared to their FA control and TS-matched WKY rats. Moreover, SH rats also demonstrated increased expression of the M1 marker in alveolar macrophages compared to FA control, as well as the M2 marker compared to controls and TS-exposed WKY rats. Conclusion The progressive tobacco smoke exposure contributes to persistent lung injury and inflammation that can be significantly enhanced by rat strain susceptibility in the genesis of COPD.

Residual Lung Injury Following HeartMate 3 Explantation for Heart Transplant

Left ventricular assist device (LVADs) are commonly used as a bridge to transplantation. The HeartMate 3 (HM 3) is the most recently approved intrathoracic LVAD. Little is known about the impact of HM 3 on adjacent lung tissue, particularly the damage that may occur during HM 3 explantation. We reviewed all HM 3 patients implanted at our center. We identified patients who underwent heart transplant (HT) and investigated post-transplant adverse events, focusing on radiological findings of the left lung (X-ray and / or computed tomography at 1week, 1 month, 3 months, and 6 months). Out of 165 HM 3 patients, 35 patients were transplanted. Mean age was 56(IQR 52, 61), 85.7% male, HT occurred at 289 days (IQR 90, 576), of LVAD support. During follow-up period of 342 days (IQR 242, 686), 33 (94.3%) survived. There were 12 (34.3%) patients who developed pneumonia, and 9 of these occurred within the first 30 days. 57% of the patients had Lt lung consolidation and 83% had left-sided pleural effusion at one week following transplant, and these findings resolved in some but not all of the cohort at 3 months (Table). In our cohort of HM 3 patients bridged to transplantation, there was excellent short and intermediate-term survival. However, a high rate of persistent left lung injury was identified following HT. Further study of the impact of these lung findings on patient morbidity is warranted.

Late Rescue Therapy with Cord-Derived Mesenchymal Stromal Cells for Established Lung Injury in Experimental Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the main complication of extreme prematurity, has lifelong consequences for lung health. Mesenchymal stromal cells (MSCs) prevent lung injury in experimental BPD in newborn rodents when given in the immediate neonatal period. Whether MSC therapy can restore normal lung growth after established lung injury in adulthood is clinically relevant, but currently unknown. Experimental BPD was achieved by exposing newborn rats to 95% O2 from postnatal days 4-14. Human umbilical cord-derived MSCs were intratracheally administered to rats (1 × 106cells/kg body weight) as a single dose at 3 or 6 months of age followed by assessment at 5 or 8 months of age, respectively. Lung alveolar structure and vessel density were histologically analyzed. O2-exposed rats exhibited persistent lung injury characterized by arrested alveolar growth with airspace enlargement and a lower vessel density at both 5 and 8 months of age compared with controls. Single-dose MSC treatment at 3 months partially attenuated O2-induced alveolar injury and restored vessel density at 5 months. Treatment with a single dose at 6 months did not attenuate alveolar injury or vessel density at 8 months. However, treatment with multiple MSC doses at 6, 6.5, 7, and 7.5 months significantly attenuated alveolar injury and improved vessel density at 8 months of age. Treatment of the adult BPD lung with MSCs has the potential to improve lung injury if administered in multiple doses or at an early stage of adulthood.

Lysosomal dysfunction is associated with persistent lung injury in dams caused by pregnancy exposure to carbon black nanoparticles

AimsCarbon black nanoparticles (CBNPs) are widely used in industrial field. Sensitive stages such as pregnancy are assumed to be more susceptible to stimulus, however whether pregnancy exposure to CBNPs (PrE-to-CBNPs) would cause long-term toxic effects in dams and the underlying mechanisms remain poorly addressed. The present study is aimed to determine the long-term toxic effects of PrE-to-CBNPs in dams. Materials and methodsThe pregnant mice were randomly divided into control group, low (21 μg/animal), medium (103 μg/animal) and high (515 μg/animal) CBNPs-treated groups. From gestational day (GD) 9 to GD18, the pregnant mice were intranasal exposed. At 49 days after parturition, lung tissues and bronchoalveolar lavage fluid (BALF) were obtained. Weight change, lung histopathology, lung ultrastructural pathology, cell count in BALF, oxidative stress/inflammatory maker and autophagy/lysosome-related protein expression were determined. Key findingsPrE-to-CBNPs caused a dose-dependent persistent lung injury in mice even 49 days after parturition, including the deteriorative lung histopathological changes, elevation of oxidative stress marker Nrf-2, HO-1 and CHOP, infiltration of macrophage and increased mRNA expression of inflammatory cytokines in the lung tissues and elevation of cells in BALF. However, PrE-to-CBNPs did not induce significant neutrophil infiltration and fibrosis. Moreover, we found that CBNPs could deposit in the lysosomes and decrease cathepsin D (an important hydrolase in lysosome), which might be associated with the dysfunction of lysosome and autophagy. SignificanceOur study demonstrated that PrE-to-CBNPs could result in long-term lung injury in dams, and lysosomal dysfunction was probably linked to this process.

Alveolar macrophage maturation is required for efficient killing of GBS in the lung

Abstract Group B Streptococcus (GBS) is the most common pathogen in neonates but rarely causes disease in adults. GBS causes pneumonia in newborns, suggesting a defect in lung innate immunity at birth. Using a novel neonatal mouse model of GBS pneumonia, we showed that newborn mice have reduced killing of GBS in the lung and more severe and persistent lung injury. Here we test the hypothesis that defects in alveolar macrophage (AM) maturation in newborns leads to GBS susceptibility. Clodronate depletion of AM from adult mice prevented GBS killing, supporting the requirement of AM for GBS protection. AM maturation and function requires GM-CSF, which is abundantly expressed in the lung. While AM maturation occurred on day 4 in WT mice, GM-CSF knockout mice (Csf2−/−) failed to develop AM. Consistent with the role of AM in GBS immunity, neonatal Csf2−/− mice had reduced GBS killing and lung macrophages failed to phagocytose GBS. Csf2−/− macrophages also had reduced expression of multiple Siglecs, cell surface receptors implicated in protection against encapsulated bacteria. Newborn lung macrophages expressed primarily Siglec-E (SigE), whereas expression of other Siglecs were only detected in more mature AM. We used SigE−/− mice to test its role in neonatal GBS pneumonia. GBS killing in SigE−/− neonates was similar to WT. However SigE−/− macrophages appeared to phagocytose GBS more efficiently in vivo, suggesting GBS may employ SigE to avoid detection by neonatal macrophages. Our data show that mature alveolar macrophages are required for protection against pulmonary GBS infection and potentially implicate the developmental regulation of macrophage Siglec expression in neonatal lung immunity.

Potassium octatitanate fibers induce persistent lung and pleural injury and are possibly carcinogenic in male Fischer 344 rats.

Potassium octatitanate fibers (K2O·8TiO2, POT fibers) are widely used as an alternative to asbestos. We investigated the pulmonary and pleural toxicity of POT fibers with reference to 2 non‐fibrous titanium dioxide nanoparticles (nTiO 2), photoreactive anatase (a‐nTiO 2) and inert rutile (r‐nTiO 2). Ten‐week‐old male F344 rats were given 0.5 mL of 250 μg/mL suspensions of POT fibers, a‐nTiO 2, or r‐nTiO 2, 8 times (1 mg/rat) over a 15‐day period by trans‐tracheal intrapulmonary spraying (TIPS). Rats were killed at 6 hours and at 4 weeks after the last TIPS dose. Alveolar macrophages were significantly increased in all treatment groups at 6 hours and at 4 weeks. At week 4, a‐nTiO 2 and r‐nTiO 2 were largely cleared from the lung whereas a major fraction of POT fibers were not cleared. In the bronchoalveolar lavage, alkaline phosphatase activity was elevated in all treatment groups, and lactate dehydrogenase (LDH) activity was elevated in the a‐nTiO 2 and POT groups. In lung tissue, oxidative stress index and proliferating cell nuclear antigen (PCNA) index were elevated in the a‐nTiO 2 and POT groups, and there was a significant elevation in C‐C motif chemokine ligand 2 (CCL2) mRNA and protein in the POT group. In pleural cavity lavage, total protein was elevated in all 3 treatment groups, and LDH activity was elevated in the a‐nTiO 2 and POT groups. Importantly, the PCNA index of the visceral mesothelium was increased in the POT group. Overall, POT fibers had greater biopersistence, induced higher expression of CCL2, and provoked a stronger tissue response than a‐nTiO 2 or r‐nTiO 2.

Weaning from prolonged veno-venous extracorporeal membrane oxygenation (ECMO) after transfer to a specialized center: a retrospective study.

Veno-venous extracorporeal membrane oxygenation (vvECMO) is increasingly used as rescue therapy in severe respiratory failure. In patients with pre-existent lung diseases or persistent lung injury weaning from vvECMO can be challenging. This study sought to investigate outcomes of patients transferred to a specialized ECMO center after prolonged ECMO therapy. We performed a retrospective analysis of all patients admitted to our medical intensive care unit (ICU) between 01/2013 and 12/2016 who were transferred from an external ICU after > 8days on vvECMO. 12 patients on ECMO for > 8days were identified. Prior to transfer, patients underwent ECMO therapy for 18 ± 9.5days. Total time on ECMO was 60 ± 46.6days. 11/12 patients could be successfully weaned from ECMO, 7/12 in the first 28days after transfer (8 ± 8.8 ECMO-free days at day 28). In 7 patients, ECMO could be terminated after at least partial lung recovery, in 4 patients after salvage lung transplant. No patient died or needed re-initiation of ECMO therapy at day 28. In summary, weaning from vvECMO was feasible even after prolonged ECMO courses and salvage lung transplant could be avoided in most cases. Patients may benefit from transfer to a specialized ECMO center.

Polysaccharide capsule allows Group B Streptococcus to avoid killing in a newborn pneumonia model

Abstract Group B Streptococcus (Streptococcus agalactiae, GBS) causes severe infections in neonates. While not a common adult pathogen, GBS is the leading cause of congenital pneumonia. To determine the molecular mechanisms of neonatal susceptibility, we developed a murine GBS pneumonia model. Neonatal, juvenile, and adult C57BL/6 mice were inoculated intranasally with 2800 CFU/g of GBS (COH1). After 7 d, survival was 100 % in adults and juveniles, with 10 % of neonates dying within 3 d after infection. Histopathological assessments showed severe lung injury scores 24 h after infection, with adult and juvenile mice demonstrating resolution of injury at 3 d post infection and normal histology after 7 d. In contrast, neonatal lungs had persistent lung injury up to 7 d post infection. By FACS, GBS induced rapid neutrophil recruitment into adult lungs and increased CD11b expression on adult lung macrophages. In neonatal lungs, GBS neither increased neutrophil numbers nor altered macrophage marker expression. Confocal imaging showed GBS in adult lungs almost entirely localized to alveolar macrophage phagolysosomes. However in neonatal lungs, GBS was only rarely phagocytosed by macrophages. These data were consistent with GBS killing data, which showed complete GBS killing within 24 h in adult and juvenile mice, but persistent GBS viability within the lung for up to 3 d in neonates. Defective GBS killing in neonates appeared to require the GBS capsule. Neonatal mice were much more efficient in killing the ΔcpsD capsule mutant compared to wild type GBS. Adult mice showed equal killing of ΔcpsD or wild type GBS. Our data suggest that the GBS capsule prevents killing by the newborn lung innate immune system, leading to neonatal disease susceptibility.