Metformin attenuates lung ischemia-reperfusion injury and necroptosis through AMPK pathway in type 2 diabetic recipient rats.

BACKGROUND: Diabetes mellitus (DM) can aggravate lung ischemia-reperfusion (I/R) injury and is a significant risk factor for recipient mortality after lung transplantation. Metformin protects against I/R injury in a variety of organs. However, the effect of metformin on diabetic lung I/R injury remains unclear. Therefore, this study aimed to observe the effect and mechanism of metformin on lung I/R injury following lung transplantation in type 2 diabetic rats. METHODS: Sprague-Dawley rats were randomly divided into the following six groups: the control + sham group (CS group), the control + I/R group (CIR group), the DM + sham group (DS group), the DM + I/R group (DIR group), the DM + I/R + metformin group (DIRM group) and the DM + I/R + metformin + Compound C group (DIRMC group). Control and diabetic rats underwent the sham operation or left lung transplantation operation. Lung function, alveolar capillary permeability, inflammatory response, oxidative stress, necroptosis and the p-AMPK/AMPK ratio were determined after 24 h of reperfusion. RESULTS: Compared with the CIR group, the DIR group exhibited decreased lung function, increased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, but decreased the p-AMPK/AMPK ratio. Metformin improved the function of lung grafts, decreased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, and increased the p-AMPK/AMPK ratio. In contrast, the protective effects of metformin were abrogated by Compound C. CONCLUSIONS: Metformin attenuates lung I/R injury and necroptosis through AMPK pathway in type 2 diabetic lung transplant recipient rats.

The dynamic response of human lungs due to underwater shock wave exposure.

Since the 19th century, underwater explosions have posed a significant threat to service members. While there have been attempts to establish injury criteria for the most vulnerable organs, namely the lungs, existing criteria are highly variable due to insufficient human data and the corresponding inability to understand the underlying injury mechanisms. This study presents an experimental characterization of isolated human lung dynamics during simulated exposure to underwater shock waves. We found that the large acoustic impedance at the surface of the lung severely attenuated transmission of the shock wave into the lungs. However, the shock wave initiated large bulk pressure-volume cycles that are distinct from the response of the solid organs under similar loading. These pressure-volume cycles are due to compression of the contained gas, which we modeled with the Rayleigh-Plesset equation. The extent of these lung dynamics was dependent on physical confinement, which in real underwater blast conditions is influenced by factors such as rib cage properties and donned equipment. Findings demonstrate a potential causal mechanism for implosion injuries, which has significant implications for the understanding of primary blast lung injury due to underwater blast exposures.

[Clinical and morphological features of lung injury long-term after SARS-CoV-2 recovery].

AIM: To study the clinical and histological profile of lung tissue in patients with persistent pulmonary disease, respiratory symptoms and CT findings after SARS-CoV-2 infection. MATERIALS AND METHODS: The study included 15 patients (7 females and 8 males) with a mean age of 57.7 years. All patients underwent laboratory tests, chest computed tomography, echocardiography, and pulmonary function tests. Pulmonary tissue and bronchoalveolar lavage samples were obtained by fibrobronchoscopy, transbronchial forceps (2 patients), and lung cryobiopsy (11 patients); open biopsy was performed in 2 patients. Cellular composition, herpesvirus DNA, SARS-CoV-2, Mycobacterium tuberculosis complex, galactomannan optical density index, and bacterial and fungal microflora growth were determined in bronchoalveolar lavage. SARS-CoV-2 was also identified in samples from the nasal mucosa, throat and feces using a polymerase chain reaction. RESULTS: The results showed no true pulmonary fibrosis in patients recovered from SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings after SARS-CoV-2 infection. The observed changes comply with the current and/or resolving infection and inflammatory process. CONCLUSION: Thus, no true pulmonary fibrosis was found in patients after SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings. The observed changes comply with the current and/or resolving infection and inflammatory process.

[Air Embolism of the Left Ventricle due to Pulmonary Stab Wound].

A man in his 50s was stabbed deeply in the back with a knife and brought to the emergency room. He was found to have a significant left hemopneumothorax. He was planned to undergo hemostatic surgery under general anesthesia. However, shortly after the change in a right lateral decubitus position, he experienced ventricular fibrillation. Hemostasis of the intercostal artery injury, the source of bleeding, and suture of the injured visceral pleura were performed under extracorporeal membrance oxgenation( ECMO). Although sinus rhythm was resumed, when positive pressure ventilation was applied to the left lung for an air leak test, ST elevation on the electrocardiogram and loss of arterial pressure occurred. A transesophageal echo revealed air accumulation in the left ventricle. It was determined that air had entered the damaged pulmonary vein from the injured bronchi due to the stab wound, leading to left ventricular puncture decompression and lower left lower lobectomy. Subsequently, his circulatory status stabilized, and ECMO was weaned off. He recovered without postoperative neurological deficits postoperatively. The mortality rate for chest trauma with systemic air embolism is very high. In cases of deep lung stab wounds, there is a possibility of systemic air embolism, so treatment should consider control of airway and vascular disruption during surgery.

The Protective Effect and Mechanism of Mild Hypothermia on Lung Injury after Cardiopulmonary Resuscitation in Pigs.

To explore the protective effect and mechanism of mild hypothermia on lung tissue damage after cardiopulmonary resuscitation in pigs. In this experiment, we electrically stimulated 16 pigs (30 ± 2 kg) for 10 min to cause ventricular fibrillation. The successfully resuscitated animals were randomly divided into two groups, a mild hypothermia group and a control group. We took arterial blood 0.5, 1, 3, and 6 h after ROSC recovery in the two groups of animals for blood gas analysis. We observed the structural changes of lung tissue under an electron microscope and calculate the wet weight/dry weight (W/D) ratio. We quantitatively analyzed the expression differences of representative inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha TNF-α)] through the ELISA test. We detected the expression levels of Bax, Bcl-2, and Caspase-3 proteins in lung tissues by Western blot. After 3 h and 6 h of spontaneous circulation was restored, compared with the control group, PaO2/FiO2 decreased significantly (P < 0.05). In addition, the pathological changes, lung W/D and lung MDA of the mild hypothermia group were better than those of the control group. The levels of IL-6 and TNF-α in the lung tissue of the mild hypothermia group were significantly lower than those of the control group (P < 0.05). The content of Caspase-3 and Bax in the mild hypothermia group was significantly lower than that of the control group. Our experiments have shown that mild hypothermia can reduce lung tissue damage after cardiopulmonary resuscitation.

[Exosomes derived from bone marrow mesenchymal stem cells regulate NF-κB pathway and reduce lung ischemia-reperfusion injury in rats by miR-335].

This study aimed to investigate the effect of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-EXO) on lung ischemia-reperfusion injury (IRI) in rats and to explore the role of miR-335. The model of rat lung IRI was established by clipping the hilum of left lung for 60 min and opening for 180 min. Forty Sprague-Dawley rats were randomly divided into sham group, IRI group, IRI+PBS group, IRI+EXO group, and IRI+miR-335 inhibitor EXO (IRI+inhibitor-EXO) group (n = 8). Rats in the sham group underwent thoracotomies without IRI. Rats in the IRI group were used to establish IRI model without any additional treatment. In the IRI+PBS, IRI+EXO, and IRI+inhibitor-EXO groups, the rats were used to establish IRI model and given PBS, EXO from BMSCs without any treatment, and EXO from BMSCs with miR-335 inhibitor treatment before reperfusion, respectively. Blood gases were analyzed during the experiment. Lung tissue wet/dry ratio (W/D), interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured at the end of reperfusion. Mitochondria were observed by electron microscopy and the Flameng scores were counted. Lung histopathology and apoptosis (TUNEL staining) were observed by light microscopy, and the lung injury scores (LIS) and apoptosis index (AI) were detected. The miR-335 expression was detected by RT-qPCR, and the expression of caspase-3, cleaved-caspase-3, caspase-9, cleaved-caspase-9, and NF-κB proteins were detected by Western blot at the end of reperfusion. The results showed that compared with the sham group, the oxygenation index, pH, and base excess (BE) were significantly lower in the IRI group and IRI+PBS group after reperfusion, whereas those indices were significantly higher in the IRI+EXO group than those in the IRI+PBS group (P < 0.05). Compared with the sham group, there were significant increases in W/D, IL-1ß, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant decreases in the SOD, miR-335 and NF-κB in the IRI group (P < 0.05). These indices in the IRI and IRI+PBS groups showed no significant differences. Compared with the IRI+PBS group, there were significant decreases in W/D, IL-1ß, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant increases in the SOD, miR-335 and NF-κB in the IRI+EXO group (P < 0.05). While, the changes of the above mentioned indices were reversed in the IRI+inhibitor-EXO group compared with IRI+EXO group, which were still better than those in the IRI+PBS group (P < 0.05). The results suggest that BMSCs-EXO could attenuate lung IRI in rats, activate NF-κB pathway, and maintain mitochondrial stability by up-regulating miR-335.

The Evolution of a Pediatric Public Health Crisis: E-cigarette or Vaping-Associated Lung Injury.

E-cigarettes and vaping products were first introduced in the United States around 2007, and quickly grew in popularity. By 2014, e-cigarettes had become the most commonly used tobacco product among youth in the United States. An e-cigarette, or vaping, product use-associated lung injury (EVALI) outbreak was identified by the Centers for Disease Control and Prevention (CDC) in 2019, with many cases in the adolescent population. The CDC opened a national database of cases and launched a multistate investigation; reported cases reached a peak in September 2019. The CDC investigation found that a vaping liquid additive, vitamin E acetate, was strongly linked to the EVALI outbreak but determined that the decline in cases was likely multifactorial. Due to decreased cases and the identification of a potential cause of the outbreak, the CDC stopped collecting data on EVALI cases as of February 2020. However, e-cigarettes and vaping products have continued to be the most popular tobacco product among youth, though state and national regulations on these products have increased since 2016. While pediatric case series and studies have shown differences in clinical presentation and medical histories between pediatric and adult EVALI cases, the fact that cases are no longer tracked at a national level limits necessary information for pediatric clinicians and researchers. We describe the available literature on the diagnosis, pathophysiology, treatment, and outcomes of EVALI in the pediatric population, and provide clinical and public health recommendations to facilitate prevention and management of EVALI specific to pediatrics.

Effectiveness of extracellular vesicles derived from hiPSCs in repairing hyperoxia-induced injury in a fetal murine lung explant model.

BACKGROUND: Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among preterm infants. Human induced pluripotent stem cells (hiPSCs) have shown promise in repairing injury in animal BPD models. Evidence suggests they exert their effects via paracrine mechanisms. We aim herein to assess the effectiveness of extracellular vesicles (EVs) derived from hiPSCs and their alveolar progenies (diPSCs) in attenuating hyperoxic injury in a preterm lung explant model. METHODS: Murine lung lobes were harvested on embryonic day 17.5 and maintained in air-liquid interface. Following exposure to 95% O2 for 24 h, media was supplemented with 5 × 106 particles/mL of EVs isolated from hiPSCs or diPSCs by size-exclusion chromatography. On day 3, explants were assessed using Hematoxylin-Eosin staining with mean linear intercept (MLI) measurements, immunohistochemistry, VEGFa and antioxidant gene expression. Statistical analysis was conducted using one-way ANOVA and Multiple Comparison Test. EV proteomic profiling was performed, and annotations focused on alveolarization and angiogenesis signaling pathways, as well as anti-inflammatory, anti-oxidant, and regenerative pathways. RESULTS: Exposure of fetal lung explants to hyperoxia induced airspace enlargement, increased MLI, upregulation of anti-oxidants Prdx5 and Nfe2l2 with decreased VEGFa expression. Treatment with hiPSC-EVs improved parenchymal histologic changes. No overt changes in vasculature structure were observed on immunohistochemistry in our in vitro model. However, VEGFa and anti-oxidant genes were upregulated with diPSC-EVs, suggesting a pro-angiogenic and cytoprotective potential. EV proteomic analysis provided new insights in regard to potential pathways influencing lung regeneration. CONCLUSION: This proof-of-concept in vitro study reveals a potential role for hiPSC- and diPSC-EVs in attenuating lung changes associated with prematurity and oxygen exposure. Our findings pave the way for a novel cell free approach to prevent and/or treat BPD, and ultimately reduce the global burden of the disease.

Distinguishing recurrence from radiation-induced lung injury at the time of RECIST progressive disease on post-SABR CT scans using radiomics.

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for patients with early-stage lung cancer who are inoperable. However, SABR causes benign radiation-induced lung injury (RILI) which appears as lesion growth on follow-up CT scans. This triggers the standard definition of progressive disease, yet cancer recurrence is not usually present, and distinguishing RILI from recurrence when a lesion appears to grow in size is critical but challenging. In this study, we developed a tool to do this using scans with apparent lesion growth after SABR from 68 patients. We performed bootstrapped experiments using radiomics and explored the use of multiple regions of interest (ROIs). The best model had an area under the receiver operating characteristic curve of 0.66 and used a sphere with a diameter equal to the lesion's longest axial measurement as the ROI. We also investigated the effect of using inter-feature and volume correlation filters and found that the former was detrimental to performance and that the latter had no effect. We also found that the radiomics features ranked as highly important by the model were significantly correlated with outcomes. These findings represent a key step in developing a tool that can help determine who would benefit from follow-up invasive interventions when a SABR-treated lesion increases in size, which could help provide better treatment for patients.

Therapeutic potential of dihydroartemisinin in mitigating radiation-induced lung injury: Inhibition of ferroptosis through Nrf2/HO-1 pathways in mice.

BACKGROUND: Radiation-induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI. METHODS: Twenty-four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF-α), transforming growth factor-ß (TGF-ß), glutathione peroxidase (GPX4), Nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed. RESULTS: DHA attenuated radiation-induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF-α and TGF-ß after irradiation. DHA may additionally stimulate the Nrf2/HO-1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI. CONCLUSION: DHA modulated the Nrf2/HO-1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI.

A Novel Peroxisome Proliferator-Activated Receptor Gamma/Nuclear Factor-Kappa B Activation Pathway is Involved in the Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemia-Reperfusion Lung Injury.

BACKGROUND: Adipose-derived stem cells (ADSCs) are well-recognized for their remarkable ability to suppress ischemia-reperfusion lung injury (IRLI). The primary objective of this investigation was to elucidate the underlying mechanism through which ADSCs exert protective effects against IRLI. METHODS: A warm hilar occlusion model in C57BL6J mice was used. Hilar occlusion was achieved for 1 hour (ischemic), and after 1 hour the occlusion was released (reperfusion) to recover for 3 hours. RNA sequencing, the physiological function, pathway activation, and expression of inflammatory cytokines were evaluated. RESULTS: Lung gas exchange and pulmonary edema were significantly improved in the IRLI/ADSCs group compared with the IRLI group. RNA sequencing results suggested that the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-kappa B (NF-κB) pathway was involved in the effect of the ADSCs. Administration of a PPARγ antagonist in the IRLI/ADSC group resulted in the deterioration of the physiological function. Furthermore, the PPARγ protein expression level decreased, the NF-κB protein expression level increased, and inflammatory cytokine parameters from lung tissue and blood sample worsened in the PPARγ antagonist-administered group. CONCLUSION: Administration of ADSCs exerted a significant protective effect against IRLI in mice, and the effect is attributed to the activation of the PPARγ/NF-κB pathway.

Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease.

Murine sickle cell disease (SCD) results in damage to multiple organs, likely mediated first by vasculopathy. While the mechanisms inducing vascular damage remain to be determined, nitric oxide bioavailability and sterile inflammation are both considered to play major roles in vasculopathy. Here, we investigate the effects of high mobility group box-1 (HMGB1), a pro-inflammatory damage-associated molecular pattern (DAMP) molecule on endothelial-dependent vasodilation and lung morphometrics, a structural index of damage in sickle (SS) mice. SS mice were treated with either phosphate-buffered saline (PBS), hE-HMGB1-BP, an hE dual-domain peptide that binds and removes HMGB1 from the circulation via the liver, 1-[4-(aminocarbonyl)-2-methylphenyl]-5-[4-(1H-imidazol-1-yl)phenyl]-1H-pyrrole-2-propanoic acid (N6022) or N-acetyl-lysyltyrosylcysteine amide (KYC) for three weeks. Human umbilical vein endothelial cells (HUVEC) were treated with recombinant HMGB1 (r-HMGB1), which increases S-nitrosoglutathione reductase (GSNOR) expression by ∼80%, demonstrating a direct effect of HMGB1 to increase GSNOR. Treatment of SS mice with hE-HMGB1-BP reduced plasma HMGB1 in SS mice to control levels and reduced GSNOR expression in facialis arteries isolated from SS mice by ∼20%. These changes were associated with improved endothelial-dependent vasodilation. Treatment of SS mice with N6022 also improved vasodilation in SS mice suggesting that targeting GSNOR also improves vasodilation. SCD decreased protein nitrosothiols (SNOs) and radial alveolar counts (RAC) and increased GSNOR expression and mean linear intercepts (MLI) in lungs from SS mice. The marked changes in pulmonary morphometrics and GSNOR expression throughout the lung parenchyma in SS mice were improved by treating with either hE-HMGB1-BP or KYC. These data demonstrate that murine SCD induces vasculopathy and chronic lung disease by an HMGB1- and GSNOR-dependent mechanism and suggest that HMGB1 and GSNOR might be effective therapeutic targets for reducing vasculopathy and chronic lung disease in humans with SCD.

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.

BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

Characterisation of quantitative imaging biomarkers for inflammatory and fibrotic radiation-induced lung injuries using preclinical radiomics.

BACKGROUND AND PURPOSE: Radiomics is a rapidly evolving area of research that uses medical images to develop prognostic and predictive imaging biomarkers. In this study, we aimed to identify radiomics features correlated with longitudinal biomarkers in preclinical models of acute inflammatory and late fibrotic phenotypes following irradiation. MATERIALS AND METHODS: Female C3H/HeN and C57BL6 mice were irradiated with 20 Gy targeting the upper lobe of the right lung under cone-beam computed tomography (CBCT) image-guidance. Blood samples and lung tissue were collected at baseline, weeks 1, 10 & 30 to assess changes in serum cytokines and histological biomarkers. The right lung was segmented on longitudinal CBCT scans using ITK-SNAP. Unfiltered and filtered (wavelet) radiomics features (n = 842) were extracted using PyRadiomics. Longitudinal changes were assessed by delta analysis and principal component analysis (PCA) was used to remove redundancy and identify clustering. Prediction of acute (week 1) and late responses (weeks 20 & 30) was performed through deep learning using the Random Forest Classifier (RFC) model. RESULTS: Radiomics features were identified that correlated with inflammatory and fibrotic phenotypes. Predictive features for fibrosis were detected from PCA at 10 weeks yet overt tissue density was not detectable until 30 weeks. RFC prediction models trained on 5 features were created for inflammation (AUC 0.88), early-detection of fibrosis (AUC 0.79) and established fibrosis (AUC 0.96). CONCLUSIONS: This study demonstrates the application of deep learning radiomics to establish predictive models of acute and late lung injury. This approach supports the wider application of radiomics as a non-invasive tool for detection of radiation-induced lung complications.

Chronic Lung Injury after COVID-19 Pneumonia: Clinical, Radiologic, and Histopathologic Perspectives.

With the COVID-19 pandemic having lasted more than 3 years, concerns are growing about prolonged symptoms and respiratory complications in COVID-19 survivors, collectively termed post-COVID-19 condition (PCC). Up to 50% of patients have residual symptoms and physiologic impairment, particularly dyspnea and reduced diffusion capacity. Studies have also shown that 24%-54% of patients hospitalized during the 1st year of the pandemic exhibit radiologic abnormalities, such as ground-glass opacity, reticular opacity, bronchial dilatation, and air trapping, when imaged more than 1 year after infection. In patients with persistent respiratory symptoms but normal results at chest CT, dual-energy contrast-enhanced CT, xenon 129 MRI, and low-field-strength MRI were reported to show abnormal ventilation and/or perfusion, suggesting that some lung injury may not be detectable with standard CT. Histologic patterns in post-COVID-19 lung disease include fibrosis, organizing pneumonia, and vascular abnormality, indicating that different pathologic mechanisms may contribute to PCC. Therefore, a comprehensive imaging approach is necessary to evaluate and diagnose patients with persistent post-COVID-19 symptoms. This review will focus on the long-term findings of clinical and radiologic abnormalities and describe histopathologic perspectives. It also addresses advanced imaging techniques and deep learning approaches that can be applied to COVID-19 survivors. This field remains an active area of research, and further follow-up studies are warranted for a better understanding of the chronic stage of the disease and developing a multidisciplinary approach for patient management.

Application of dose-gradient function in reducing radiation induced lung injury in breast cancer radiotherapy.

OBJECTIVE: Try to create a dose gradient function (DGF) and test its effectiveness in reducing radiation induced lung injury in breast cancer radiotherapy. MATERIALS AND METHODS: Radiotherapy plans of 30 patients after breast-conserving surgery were included in the study. The dose gradient function was defined as DGH=VDVp3, then the area under the DGF curve of each plan was calculated in rectangular coordinate system, and the minimum area was used as the trigger factor, and other plans were triggered to optimize for area reduction. The dosimetric parameters of target area and organs at risk in 30 cases before and after re-optimization were compared. RESULTS: On the premise of ensuring that the target dose met the clinical requirements, the trigger factor obtained based on DGF could further reduce the V5, V10, V20, V30 and mean lung dose (MLD) of the ipsilateral lung in breast cancer radiotherapy, P < 0.01. And the D2cc and mean heart dose (MHD) of the heart were also reduced, P < 0.01. Besides, the NTCPs of the ipsilateral lung and the heart were also reduced, P < 0.01. CONCLUSION: The trigger factor obtained based on DGF is efficient in reducing radiation induced lung injury in breast cancer radiotherapy.

Noninvasive Quantification of Radiation-Induced Lung Injury Using a Targeted Molecular Imaging Probe.

PURPOSE: Radiation-induced lung injury (RILI) is a progressive inflammatory process seen after irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Here, we sought to noninvasively quantify RILI using a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. METHODS AND MATERIALS: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe, to characterize the development of RILI and to assess disease mitigation after losartan treatment. The human analog probe 68Ga-CBP8, targeting type 1 collagen, was tested on excised human lung tissue containing RILI and was quantified via autoradiography. 68Ga-CBP8 positron emission tomography was used to assess RILI in vivo in 6 human subjects. RESULTS: Murine models demonstrated that probe signal correlated with progressive RILI severity over 6 months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding versus unirradiated control tissue, and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. CONCLUSIONS: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.

Early, non-invasive detection of radiation-induced lung injury using PET/CT by targeting CXCR4.

PURPOSE: Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy (RT) for thoracic malignancies and we currently lack established methods for the early detection of RILI. In this study, we synthesized a new tracer, [18F]AlF-NOTA-QHY-04, targeting C-X-C-chemokine-receptor-type-4 (CXCR4) and investigated its feasibility to detect RILI. METHODS: An RILI rat model was constructed and scanned with [18F]AlF-NOTA-QHY-04 PET/CT and [18F]FDG PET/CT periodically after RT. Dynamic, blocking, autoradiography, and histopathological studies were performed on the day of peak uptake. Fourteen patients with radiation pneumonia, developed during or after thoracic RT, were subjected to PET scan using [18F]AlF-NOTA-QHY-04. RESULTS: The yield of [18F]AlF-NOTA-QHY-04 was 28.5-43.2%, and the specific activity was 27-33 GBq/µmol. [18F]AlF-NOTA-QHY-04 was mainly excreted through the kidney. Significant increased [18F]AlF-NOTA-QHY-04 uptake in the irradiated lung compared with that in the normal lung in the RILI model was observed on day 6 post-RT and peaked on day 14 post-RT, whereas no apparent uptake of [18F]FDG was shown on days 7 and 15 post-RT. MicroCT imaging did not show pneumonia until 42 days post-RT. Significant intense [18F]AlF-NOTA-QHY-04 uptake was confirmed by autoradiography. Immunofluorescence staining demonstrated expression of CXCR4 was significantly increased in the irradiated lung tissue, which correlated with results obtained from hematoxylin-eosin and Masson's trichrome staining. In 14 patients with radiation pneumonia, maximum standardized uptake values (SUVmax) were significantly higher in the irradiated lung compared with those in the normal lung. SUVmax of patients with grade 2 RILI was significantly higher than that of patients with grade 1 RILI. CONCLUSION: This study indicated that [18F]AlF-NOTA-QHY-04 PET/CT imaging can detect RILI non-invasively and earlier than [18F]FDG PET/CT in a rat model. Clinical studies verified its feasibility, suggesting the clinical potential of [18F]AlF-NOTA-QHY-04 as a PET/CT tracer for early monitoring of RILI.

Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management.

Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.

Predicting Radiation-Induced Lung Injury in Patients With Lung Cancer: Challenges and Opportunities.

Radiation-induced lung injury (RILI) is one of the main dose-limiting toxicities in radiation therapy (RT) for lung cancer. Approximately 10% to 20% of patients show signs of RILI of variable severity. The reason for the wide range of RILI severity and the mechanisms underlying its development are only partially understood. A number of clinical risk factors have been identified that can aid in clinical decision making. Technological advancements in RT and the use of strict organ-at-risk dose constraints have helped to reduce RILI. Predicting patients at risk for RILI may be further improved with a combination of cytokine assessments, γH2AX-assays in leukocytes, or epigenetic markers. A complicating factor is the lack of an objective definition of RILI. Tools such as computed tomography densitometry, fluorodeoxyglucose-positron emission tomography uptake, changes in lung function measurements, and exhaled breath analysis can be implemented to better define and quantify RILI. This can aid in the search for new biomarkers, which can be accelerated by omics techniques, single-cell RNA sequencing, mass cytometry, and advances in patient-specific in vitro cell culture models. An objective quantification of RILI combined with these novel techniques can aid in the development of biomarkers to better predict patients at risk and allow personalized treatment decisions.