Advances in multimodal imaging of lung injury

Yang K., Liu Y., Deng M., Wang P., Cheng D., Li S., He L.

The cellular endoplasmic reticulum (ER) is responsible for various functions, including protein synthesis, folding, distribution, and calcium ion storage. Studies have linked ER stress with acute lung injury (ALI), which can result in oxidative stress and even cell death. Peroxynitrite (ONOO−) is a well-known reactive oxygen species (ROS) that contributes to various physiological and pathological processes in oxidative stress diseases. To understand the role of ER ONOO− in ALI, it is crucial to accurately measure its level in the ER. Unfortunately, there is currently no probe available to detect ER ONOO− in an ALI model. To address this, we developed three near-infrared (NIR) fluorescent probes (DCM-F-ONOO, DCM-Cl-ONOO, and DCM-Br-ONOO) for the detection of ONOO− using pentafluorobenzenesulfonate (PFBS) moieties as fluorescence quenchers. Through comprehensive testing, we selected DCM-Br-ONOO as the best NIR fluorescent probe due to its rapid response (within 3 min), high selectivity, good sensitivity (LOD = 2.3 nM), and approximately 66-fold enhanced response to ONOO− in fluorescence intensity. The probe was successfully applied to detect changes in ONOO− levels induced by different drugs in the ER of living cells. Importantly, a significant increase in the level of ONOO− was observed in the ER of an ALI cell model (4.5-fold) and an ALI mouse model (2.5-fold) using the probe, which is essential for understanding the role of ONOO− in ER-associated diseases. Using DCM-Br-ONOO as a probe, present work further validated that the elevated levels of ONOO− secretion were accompanied by the ALI progressed. These findings may provide valuable results for figuring out the biological roles that ONOO− played in ALI.

Pei J., Cheng K., Liu T., Gao M., Wang S., Xu S., Guo Y., Ma L., Li W., Wang B., Yu J., Liu J.

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. 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. 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. 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.

Bosch de Basea Gomez M., Thierry-Chef I., Harbron R., Hauptmann M., Byrnes G., Bernier M., Le Cornet L., Dabin J., Ferro G., Istad T.S., Jahnen A., Lee C., Maccia C., Malchair F., Olerud H., et. al.

AbstractOver one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1–2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses.

Abston E., Zhou I., Saenger J., Shuvaev S., Akam E.A., Esfahani S., Hariri L., Rotile N., Crowley E., Montesi S., Humblet V., Arabasz G., Khandekar M., Catana C., Fintelmann F., et. al.

AbstractRationaleRadiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following 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.ObjectiveTo noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI.MethodsUsing 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 following losartan treatment. The human analog probe targeted against type 1 collagen,68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally,68Ga-CBP8 PET was used to assess RILIin vivoin six human subjects.ResultsMurine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant68Ga-CBP8 uptake in areas of RILI and minimal background uptake.ConclusionsThese 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.Clinical trial registered withwww.clinicaltrials.gov(NCT04485286,NCT03535545)

Lucassen R.T., Jafari M.H., Duggan N.M., Jowkar N., Mehrtash A., Fischetti C., Bernier D., Prentice K., Duhaime E.P., Jin M., Abolmaesumi P., Heslinga F.G., Veta M., Duran-Mendicuti M.A., Frisken S., et. al.

Sanwal R., Mintsopoulos V., Ditmans M., Lang A., Latreille E., Ghaffari S., Khosraviani N., Karshafian R., Leong-Poi H., Hwang D.M., Brochard L., Goffi A., Slutsky A.S., Lee W.L.

In acute lung injury, the lung endothelial barrier is compromised. Loss of endothelial barrier integrity occurs in association with decreased levels of the tight junction protein claudin-5. Restoration of their levels by gene transfection may improve the vascular barrier but how to limit transfection solely to regions of the lung that are injured is unknown. We hypothesized that thoracic ultrasound in combination with intravenous microbubbles (USMB) could be used to achieve regional gene transfection in injured lung regions and improve endothelial barrier function. Since air blocks ultrasound energy, insonation of the lung is only achieved at areas of lung injury (edema, atelectasis); healthy lung is spared. Cavitation of the microbubbles achieves local tissue transfection. Here we demonstrate successful ultrasound-microbubble (USMB)-mediated gene transfection in the injured lungs of mice. After thoracic insonation, transfection was confined to the lung and only occurred in the setting of injured (but not healthy) lung. In a mouse model of acute lung injury, we observed down-regulation of endogenous claudin-5 and an acute improvement in lung vascular leakage and in oxygenation after claudin-5-over-expression by transfection. The improvement occurred without any impairment of the immune response as measured by pathogen clearance, alveolar cytokines and lung histology. In conclusion, USMB-mediated transfection targets injured lung regions and is a novel approach in the treatment of lung injury.

Marquis K.M., Hammer M.M., Steinbrecher K., Henry T.S., Lin C., Shifren A., Raptis C.A.

Musch G.

This review focuses on methods to image acute lung inflammation with Positron Emission Tomography (PET). Four approaches are discussed that differ for biologic function of the PET reporter probe, radiotracer employed, and the specific aspect of the inflammatory response that is targeted. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is an enzyme substrate whose uptake is used to measure the metabolic activation of inflammatory cells during acute lung injury in the noncancerous lung. H215O and radiolabeled plasma proteins are inert molecules with the same physical characteristics as their nonradioactive counterparts and are used to measure edema and vascular permeability. Tagged enzyme or receptor inhibitors are used to probe expression of these targets induced by inflammatory stimuli. Lastly, cell-specific tracers are being developed to differentiate the cell types that contribute to the inflammatory response. Taken together, these methods cast PET imaging as a versatile and quantitative tool to measure inflammation in vivo noninvasively during acute and ventilator-induced lung injury.

Zhang Z., Wang Z., Luo T., Yan M., Dekker A., De Ruysscher D., Traverso A., Wee L., Zhao L.

Purpose To develop a deep learning model that combines CT and radiation dose (RD) images to predict the occurrence of radiation pneumonitis (RP) in lung cancer patients who received radical (chemo)radiotherapy. Methods CT, RD images and clinical parameters were obtained from 314 retrospectively-collected patients (training set) and 35 prospectively-collected patients (test-set-1) who were diagnosed with lung cancer and received radical radiotherapy in the dose range of 50 Gy and 70 Gy. Another 194 (60 Gy group, test-set-2) and 158 (74 Gy group, test-set-3) patients from the clinical trial RTOG 0617 were used for external validation. A ResNet architecture was used to develop a prediction model that combines CT and RD features. Thereafter, the CT and RD weights were adjusted by using 40 patients from test-set-2 or 3 to accommodate cohorts with different clinical settings or dose delivery patterns. Visual interpretation was implemented using a gradient-weighted class activation map (grad-CAM) to observe the area of model attention during the prediction process. To improve the usability, ready-to-use online software was developed. Results The discriminative ability of a baseline trained model had an AUC of 0.83 for test-set-1, 0.55 for test-set-2, and 0.63 for test-set-3. After adjusting CT and RD weights of the model using a subset of the RTOG-0617 subjects, the discriminatory power of test-set-2 and 3 improved to AUC 0.65 and AUC 0.70, respectively. Grad-CAM showed the regions of interest to the model that contribute to the prediction of RP. Conclusion A novel deep learning approach combining CT and RD images can effectively and accurately predict the occurrence of RP, and this model can be adjusted easily to fit new cohorts.

Astley J.R., Biancardi A.M., Hughes P.J., Marshall H., Collier G.J., Chan H., Saunders L.C., Smith L.J., Brook M.L., Thompson R., Rowland‐Jones S., Skeoch S., Bianchi S.M., Hatton M.Q., Rahman N.M., et. al.

Mannes P.Z., Barnes C.E., Biermann J., Latoche J.D., Day K.E., Zhu Q., Tabary M., Xiong Z., Nedrow J.R., Izar B., Anderson C.J., Villanueva F.S., Lee J.S., Tavakoli S.

The lack of techniques for noninvasive imaging of inflammation has challenged precision medicine management of acute respiratory distress syndrome (ARDS). Here, we determined the potential of positron emission tomography (PET) of chemokine-like receptor-1 (CMKLR1) to monitor lung inflammation in a murine model of lipopolysaccharide-induced injury. Lung uptake of a CMKLR1-targeting radiotracer, [ 64 Cu]NODAGA-CG34, was significantly increased in lipopolysaccharide-induced injury, correlated with the expression of multiple inflammatory markers, and reduced by dexamethasone treatment. Monocyte-derived macrophages, followed by interstitial macrophages and monocytes were the major CMKLR1-expressing leukocytes contributing to the increased tracer uptake throughout the first week of lipopolysaccharide-induced injury. The clinical relevance of CMKLR1 as a biomarker of lung inflammation in ARDS was confirmed using single-nuclei RNA-sequencing datasets which showed significant increases in CMKLR1 expression among transcriptionally distinct subsets of lung monocytes and macrophages in COVID-19 patients vs. controls. CMKLR1-targeted PET is a promising strategy to monitor the dynamics of lung inflammation and response to anti-inflammatory treatment in ARDS.

Volpicelli G., Fraccalini T., Cardinale L., Stranieri G., Senkeev R., Maggiani G., Pacielli A., Basile D.

Lung ultrasound (LUS) scanning is useful to diagnose and assess the severity of pulmonary lesions during COVID-19-related ARDS (CoARDS). A conventional LUS score is proposed to measure the loss of aeration during CoARDS. However, this score was validated during the pre-COVID-19 era in patients with ARDS in the ICU and does not consider the differences with CoARDS. An alternative LUS method is based on grading the percentage of extension of the typical signs of COVID-19 pneumonia on the lung surface (LUSext).Is LUSext feasible in patients with COVID-19 at the onset of disease, and does it correlate with the volumetric measure of severity of COVID-19 pneumonia lesions at CT scan (CTvol)?This observational study enrolled a convenience sampling of patients in the ED with confirmed COVID-19 whose condition demonstrated pneumonia at bedside LUS and CT scan. LUSext was visually quantified. All CT scan studies were analyzed retrospectively by a specifically designed software to calculate the CTvol. The correlation between LUSext and CTvol, and the correlations of each score with Pao2/Fio2 ratio were calculated.We analyzed data from 179 patients. Feasibility of LUSext was 100%. Time to perform LUS scan was 5 ± 1.5 mins. LUSext and CTvol were correlated positively (R = 0.67; P < .0001). Both LUSext and CTvol showed negative correlation with Pao2/Fio2 ratio (R = -0.66 and R = -0.54; P < .0001, respectively).LUSext is a valid measure of the severity of the lesions when compared with the CT scan. Not only are LUSext and CTvol correlated, but they also have similar inverse correlation with the severity of respiratory failure. LUSext is a practical and simple bedside measure of the severity of pneumonia in CoARDS, whose clinical and prognostic impact need to be investigated further.

Serrano Gotarredona M.P., Navarro Herrero S., Gómez Izquierdo L., Rodríguez Portal J.A.

Exposure to smoke is associated with the development of diseases of the airways and lung parenchyma. Apart from chronic obstructive pulmonary disease (COPD), in some individuals, tobacco smoke can also trigger mechanisms of interstitial damage that result in various pathological changes and pulmonary fibrosis. A causal relation has been established between tobacco smoke and a group of entities that includes respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), Langerhans cell histiocytosis (LCH), and acute eosinophilic pneumonia (AEP). Smoking is considered a risk factor for idiopathic pulmonary fibrosis (IPF); however, the role and impact of smoking in the development of this differentiated clinical entity, which has also been called combined pulmonary fibrosis and emphysema (CPFE) as well as nonspecific interstitial pneumonia (NIP), remains to be determined. The definition of smoking-related interstitial fibrosis (SRIF) is relatively recent, with differentiated histological characteristics. The likely interconnection between the mechanisms involved in inflammation and pulmonary fibrosis in all these processes often results in an overlapping of clinical, radiological, and histological features in the same patient that can sometimes lead to radiological patterns of interstitial lung disease that are impossible to classify. For this reason, a combined approach to diagnosis is recommendable. This combined approach should be based on the joint interpretation of the histological and radiological findings while taking the clinical context into consideration. This paper aims to describe the high-resolution computed tomography (HRCT) findings in this group of disease entities in correlation with the clinical manifestations and histological changes underlying the radiological pattern.

Tanaka N., Kunihiro Y., Kawano R., Yujiri T., Ueda K., Gondo T., Kobayashi T., Matsumoto T.

To differentiate among infectious diseases, drug-induced lung injury (DILI) and pulmonary infiltration due to underlying malignancy (PIUM) based on high-resolution computed tomographic (HRCT) findings from patients with hematological malignancies who underwent chemotherapy or hematopoietic stem cell transplantation. A total of 221 immunocompromised patients with hematological malignancies who had proven chest complications (141 patients with infectious diseases, 24 with DILI and 56 with PIUM) were included. Two chest radiologists evaluated the HRCT findings, including ground-glass opacity, consolidation, nodules, and thickening of bronchovascular bundles (BVBs) and interlobular septa (ILS). After comparing these CT findings among the three groups using the χ2test, multiple logistic regression analyses (infectious vs noninfectious diseases, DILI vs non-DILI, and PIUM vs non-PIUM) were performed to detect useful indicators for differentiation. Significant differences were detected in many HRCT findings by the χ2 test. The results from the multiple logistic regression analyses identified several indicators: nodules without a perilymphatic distribution [p = 0.012, odds ratio (95% confidence interval): 4.464 (1.355–11.904)], nodules with a tree-in-bud pattern [p = 0.011, 8.364 (1.637–42.741)], and the absence of ILS thickening[p = 0.003, 3.621 (1.565–8.381)] for infectious diseases, the presence of ILS thickening [p = 0.001, 7.166 (2.343–21.915)] for DILI, and nodules with a perilymphatic distribution [p = 0.011, 4.256 (1.397–12.961)] and lymph node enlargement (p = 0.008, 3.420 (1.385–8.441)] for PIUM. ILS thickening, nodules with a perilymphatic distribution, tree-in-bud pattern, and lymph node enlargement could be useful indicators for differentiating among infectious diseases, DILI, and PIUM in patients with hematological malignancies.

McIntosh M.J., Kooner H.K., Eddy R.L., Jeimy S., Licskai C., Mackenzie C.A., Svenningsen S., Nair P., Yamashita C., Parraga G.

Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function.Does 129Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response?MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28 days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and 28.Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P < .001), and peripheral airway resistance (P = .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n = 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P < .001) and day 0 CT scan mucus score (P < .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection.129Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab.ClinicalTrials.gov; No.: NCT03733535; URL: www.gov.