Lung function and systemic inflammation associated with short-term air pollution exposure in chronic obstructive pulmonary disease patients in Beijing, China.

BACKGROUND: Exposure to air pollution is associated with chronic obstructive pulmonary disease (COPD). However, findings on the effects of air pollution on lung function and systemic inflammation in Chinese COPD patients are inconsistent and scarce. This study aims to evaluate the effects of ambient air pollution on lung function parameters and serum cytokine levels in a COPD cohort in Beijing, China. METHODS: We enrolled COPD participants on a rolling basis from December 2015 to September 2017 in Beijing, China. Follow-ups were performed every 3 months for each participant. Serum levels of 20 cytokines were detected every 6 months. Hourly ambient pollutant levels over the same periods were obtained from 35 monitoring stations across Beijing. Geocoded residential addresses of the participants were used to estimate daily mean pollution exposures. A linear mixed-effect model was applied to explore the effects of air pollutants on health in the first-year of follow-up. RESULTS: A total of 84 COPD patients were enrolled at baseline. Of those, 75 COPD patients completed the first-year of follow-up. We found adverse cumulative effects of particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO) on the forced vital capacity % predicted (FVC % pred) in patients with COPD. Further analyses illustrated that among COPD patients, air pollution exposure was associated with reduced levels of serum eotaxin, interleukin 4 (IL-4) and IL-13 and was correlated with increased serum IL-2, IL-12, IL-17A, interferon γ (IFNγ), monocyte displacing protein 1 (MCP-1) and soluble CD40 ligand (sCD40L). CONCLUSION: Acute exposures to PM2.5, NO2, SO2 and CO were associated with a reduction in FVC % pred in COPD patients. Furthermore, short-term exposure to air pollutants increased systemic inflammation in COPD patients; this may be attributed to increased Th1 and Th17 cytokines and decreased Th2 cytokines.

Effects of COVID-19 infection in patients with autoimmune pulmonary alveolar proteinosis: a single-center study.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease. COVID-19 is associated with worse prognosis in previous lung diseases patients. But the prognosis of aPAP patients after infection with COVID-19 is unclear. In December 2022, China experienced a large-scale outbreak of Omicron variant of the SARS-CoV-2. In this study, we aim to explore the clinical outcomes of aPAP patients infected with COVID-19. RESULTS: A total of 39 aPAP patients were included in this study. 30.77% patients had a decrease in oxygen saturation after COVID-19 infection. We compared the two groups of patients with or without decreased oxygen saturation after COVID-19 infection and found that patients who had previous oxygen therapy (decreased oxygen saturation vs. non decreased oxygen saturation: 6/12 vs. 4/27, P = 0.043), with lower baseline arterial oxygen partial pressure (74.50 ± 13.61 mmHg vs. 86.49 ± 11.92 mmHg, P = 0.009), lower baseline DLCO/VA% [77.0 (74.3, 93.6) % vs. 89.5 (78.2, 97.4) %, P = 0.036], shorter baseline 6MWD [464 (406, 538) m vs. 532 (470, 575) m, P = 0.028], higher disease severity score (P = 0.017), were more likely to have decreased oxygen saturation after COVID-19 infection. CONCLUSION: aPAP patients with poor baseline respiration have a higher probability of hypoxia after COVID-19 infection, but fatal events were rare.

Determinants of Progression and Mortality in Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined. RESEARCH QUESTION: Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis? STUDY DESIGN AND METHODS: The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis. RESULTS: VEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV1 faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival. INTERPRETATION: Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03193892; URL: www. CLINICALTRIALS: gov.

[Effects of different severities of hypoxia-ischemia on brain injury in neonatal rats].

OBJECTIVE: To compare the features of brain injury in neonatal rats with different severities of hypoxia-ischemia (HI), and explore the role of microglial activation and cytokines. METHODS: One hundred and twenty 7-day-old rats were randomized to three groups: sham control, mild HI, and severe HI. The rats in the HI groups were subjected to right carotid artery occlusion and 8% oxygen hypoxia exposure (40 minutes, 34.5 Celsius degree in the mild HI group; 65 minutes, 35.5 Celsius degree in the severe HI group). MRI, microtubule associated protein (MAP2) and TUNEL staining were used to confirm the severity of brain injury. Changes in expression of activated microglia (ED1) and signs of cytokine involvement or oxidative stress (TNF-alpha, nitrotyrosine) were assessed immunohistochemically. RESULTS: In the mild HI group, MRI scans demonstrated increased T2 values in the ipsilateral subcortical white matter and a slight loss of T2 values in the cortex, corresponding to a medium loss of MAP2 in the ipsilateral cortex. There was an increase in the number of TUNEL positive cells compared to the control group within the subcortical white matter. In the severe HI group, the T2 value increased in the majority of the hemisphere, corresponding to a severe loss of staining for MAP2 in the ispilateral hemisphere. The number of TUNEL positive cells significantly increased in the ipsilateral cortex and white matter. In the mild HI group, ED1, TNF-alpha and nitrotyrosine expression increased only in the acute stage and was only observed in subcortical white matter. In contrast, after severe HI, the increase in ED1, TNF-alpha and nitrotyrosine expression was observed in the whole ipsilateral hemisphere and prolonged for weeks. CONCLUSIONS: Following a mild HI a relatively selective white matter injury compares to the pannecrosis in the cortex and white matter following a severe HI. Microglial activation and over-expression of cytokines might contribute to the development of hypoxic-ischemic brain damage.

Characterization of CT scans of patients with Birt-Hogg-Dubé syndrome compared with those of Chinese patients with non-BHD diffuse cyst lung diseases.

BACKGROUND AND OBJECTIVE: The purpose of this study was to create a practical CT-based algorithm to differentiate Birt-Hogg-Dubé (BHD) syndrome from other diffuse cystic lung diseases (DCLD). METHODS: The study was a retrospective review of the CT images of 33 patients with BHD syndrome, 33 patients with LAM, and 23 patients with NBNL (non-BHD and non-LAM) among DCLD patients. On the basis of the data collected, the CT images were reviewed again to evaluate the characteristics (size, number, distribution, and morphology) of pulmonary cysts. RESULTS: Lower lung-predominant cysts were more likely to be found in patients with BHD syndrome than in patients with LAM or in the NBNL DCLD group. In the axial distribution, 18 of 33 patients in BHD group had cysts that were predominantly near the mediastinum, and all the patients in the LAM and NBNL DCLD groups had diffuse cysts. The appearance of fusiform cysts was more easily observed in patients in the BHD group. In total, 58% patients in the BHD group had less than 50 lung cysts, while all patients in the non-BHD group had more than 50 lung cysts. The biggest cyst was located in the lower lobe in 28 of 33 patients in the BHD group, while 11 of 33 patients in LAM group and 10 patients in the NBNL DCLD group had the biggest cyst in the lower lobe. CONCLUSION: The pulmonary cysts in patients with BHD tended to be fusiform, less numerous and located predominantly in the lower lobe and near the mediastinum. These radiologic pulmonary features could assist physicians in differentiating BHD from other DCLDs.

Inhaled granulocyte-macrophage colony stimulating factor for mild-to-moderate autoimmune pulmonary alveolar proteinosis - a six month phase II randomized study with 24 months of follow-up.

BACKGROUND: Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by inhaled granulocyte-macrophage colony stimulating factor (GM-CSF) is considered safe and effective. Evidence of benefit from GM-CSG inhalation for mild to moderate aPAP patients is limited. METHODS: In this multicenter, randomized, open-labeled clinical trial, 36 aPAP patients with mild to moderate disease severity were randomized into either the GM-CSF treatment group or control group. Inhaled GM-CSF was prescribed for 6 months, and patients received follow-up for another 18 months without treatment. Physiological features of the patients were analyzed. RESULTS: There were 36 patients (19 in the treatment group, 17 in the control group) included. There were no significant differences in the primary endpoints as measured by the change of alveolar arterial oxygen gradient (A-aDO2) from the baseline values to the values obtained during treatment or during the following 18-month non-treatment observation period [control group vs. treatment group: 0.51 ± 12.09 mmHg vs. -0.35 ± 13.76 mmHg, p = 0.848 (3 month); 1.85 ± 11.21 mmHg vs. 7.31 ± 8.81 mmHg, p = 0.146 (6 months); 6.05 ± 11.14 mmHg vs. 6.61 ± 10.64 mmHg, p = 0.899 (24 months)]). Percentage of diffusion capacity predicted (DLCO%) and percentage of total lung capacity predicted (TLC%), however, were significantly improved in the treatment group by the end of the study (P = 0.010 and 0.027). St. George Respiratory questionnaire (SGRQ) scores were better after 6 months treatment with GM-CSF compared to the control group, and the benefits of treatment were maintained throughout the observation period. No severe side effects were observed during the study. CONCLUSION: Six months of inhaled GM-CSF treatment had no effect on the alveolar-arterial oxygen gradient in patients with mild to moderate pulmonary alveolar proteinosis. There were changes in some clinical or laboratory measures, but no clinically important changes were noted at the end of study. (Clinical Trial Registry: NCT02243228, Registered on September 17, 2014, https://www.clinicaltrials.gov/ct2/show/NCT02243228?term=NCT02243228&draw=2&rank=1 ).

Magnetic resonance imaging of differential gray versus white matter injury following a mild or moderate hypoxic-ischemic insult in neonatal rats.

Selective white matter injury in the pre-mature infants suggests it has a greater susceptibility to hypoxia-ischemia. To investigate whether white matter injury would predominate following a mild hypoxic-ischemic insult, 7-day-old rats underwent either mild or moderate hypoxia-ischemia and magnetic resonance imaging 24 h later. Mild and moderate hypoxia-ischemia were produced by unilateral carotid artery occlusion plus exposure to hypoxia for either 45-50 or 90 min at ambient temperatures of 34.5 or 35.5 degrees C, respectively. Following mild hypoxia-ischemia, there was a significant increase in T(1) and T(2) within periventricular white matter (e.g. corpus callosum) in the hemisphere ipsilateral to the occlusion compared to that contralaterally and less of an increase within gray matter (e.g. cortex and striatum). This corresponded to relatively selective white matter injury detected histologically. Following a moderate hypoxia-ischemia, both gray and white matter was severely injured with marked increases in T(1) and T(2) occurring in both white and gray matter regions ipsilateral to the hypoxia-ischemia. We conclude that a mild insult, consisting of a short duration of hypoxia-ischemia at a slightly lower body temperature than a moderate hypoxic-ischemic insult, produces enhanced injury in white matter and a relative sparing of gray matter.

Mild cerebral hypoxia-ischemia produces a sub-acute transient inflammatory response that is less selective and prolonged after a substantial insult.

Cerebral ischemia initiates various injurious processes including neuroinflammatory responses such as activation of microglia and increases in cytokine and nitric oxide release. Evidence primarily from in vitro studies, indicates that neuroinflammatory effects can be either beneficial or harmful, possibly related to stimulus strength. We investigated using in vivo models, the effect of a mild or substantial cerebral hypoxia-ischemia on: cerebral microglial/macrophage activation (ED1), pro-inflammatory cytokines (tumor necrosis factor-alpha), nitrosative stress (nitrotyrosine) and permanent brain damage. A mild insult produced a transient (1-2 days post) increase in activated microglia/macrophages within subcortical white and not gray matter but transiently increased cytokine or nitrotyrosine expression in cortex and not white matter. There was also prolonged scattered cell death in cortex and white matter over weeks along with loss of myelin/axons and cortical atrophy at 4 weeks post-insult. In contrast, a substantial insult produced white and gray matter necrosis, cyst formation and atrophy, along with increases in tumor necrosis factor and nitrotyrosine staining within both white and gray matter starting at 1-2 days post-insult. Microglial/macrophage staining was increased starting at 1-week post a substantial insult and remained elevated for weeks thereafter. Thus, a transient neuroinflammatory response occurs following a mild insult whereas prolonged scattered cell death occurs for weeks, particularly in white matter. Insult severity also affects the progression of the neuroinflammatory response, which is prolonged after a substantial insult. Effective therapy will need to be customized for insult severity and timing; and, monitoring the injury processes with imaging or biomarkers may help guide treatment.

Cerebral expression of DNA repair protein, Ku70, and its association with cell proliferation following cerebral hypoxia-ischemia in neonatal rats.

We hypothesized that increased Ku70 expression could be involved in recovery following cerebral hypoxia-ischemia. We investigated the progression of cerebral alterations in Ku70 expression at different time points (24 h, 72 h, 1 week, 4 weeks and 8 weeks) after hypoxia-ischemia (right carotid artery occlusion plus 1.5h of hypoxia) in neonatal rats. To determine whether in addition to its known role of DNA repair, Ku70 was associated with cell death or cell proliferation we performed double staining for Ku70 and DNA fragmentation or bromodeoxyuridine, respectively. The results show that Ku70 expression was increased in the infarct core and peri-infarct regions at 24h following hypoxia-ischemia. The increased Ku70 expression was transient in the infarct core with a loss of Ku70 positive cells over days. In contrast, in the peri-infarct region the expression of Ku70 remained increased at chronic times 8 weeks following the insult. Cells positive for DNA fragmentation were not co-localized with cells positive for Ku70 after an insult. However, most of the cells positive for bromodeoxyuridine indicative of cell proliferation were positive for Ku70 in the peri-infarct region at 8 weeks after the insult. Considering the roles of Ku70 in DNA repair or inhibiting apoptosis and its co-localization within cells that had undergone proliferation, Ku70 may be considered a potential novel target to enhance recovery following hypoxia-ischemia.

Differential progression of magnetization transfer imaging changes depending on severity of cerebral hypoxic-ischemic injury.

We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive for detecting cerebral ischemic injury in white matter of neonatal brain. We compared the progression of changes in T(2) and the MT ratio (MTR) after cerebral hypoxic-ischemic insults of differing severity in neonatal rats. Magnetization transfer imaging parameters were first optimized, and then MTR and T(2) maps were acquired at various times after a mild (rather selective white matter) or substantial insult produced by unilateral cerebral hypoxia-ischemia. Depending on insult severity, time after insult, and region (e.g., subcortical white matter or cortex), cerebral hypoxia-ischemia produced reductions in MTR and an increase in T(2). The exception was acutely at 1 to 5 h at which time points MTR was reduced ipsilaterally in white matter, whereas T(2) was not affected significantly. Progression of imaging changes differed in rats grouped according to whether gross damage was present after chronic recovery. Behavioral changes were generally associated with chronic reductions in MTR and gross brain damage. Magnetization transfer imaging was capable of early detection of hypoxic-ischemic injury and particularly sensitive for identifying the progression of cerebral injury in white matter. Magnetization transfer ratio has potential for assisting with early diagnosis and treatment assessment for infants affected by perinatal hypoxia-ischemia.

Evolution of magnetic resonance imaging changes associated with cerebral hypoxia-ischemia and a relatively selective white matter injury in neonatal rats.

We hypothesized that a combination of quantitative magnetic resonance imaging (MRI) sequences would detect a differential evolution of hypoxic-ischemic changes in white matter compared with gray matter in a recently developed model of unilateral mild cerebral hypoxia-ischemia in the 7-d-old rat. Using this model, which involved unilateral carotid artery occlusion and exposure to hypoxia for 45-50 min, maps of apparent diffusion coefficients of water (ADC), T1, T2, and cerebral blood flow (CBF) were acquired either before hypoxia-ischemia or at 1, 24, or 48 h and at 7 d post-hypoxia-ischemia followed by brain processing for histology. At 1 h post-hypoxia-ischemia, MRI changes in white matter ipsilateral to the hypoxia-ischemia were not as pronounced as those in gray matter. However, increases in T1, T2 and ADC and decreases in CBF within white matter enhanced over time, with changes being maximal at 48 h post-hypoxia-ischemia, whereas changes in the cortical gray matter normalized over this time. By 7 d post-hypoxia-ischemia, there were no differences in ADC, T1, T2, or CBF between hemispheres despite there being histologic changes in white matter within the hypoxic-ischemic hemisphere including increased glial proliferation and reactivity, reduced myelin basic protein, and increased cell death. The results demonstrate that increases in ADC and T2 observed subacutely in the days following hypoxia-ischemia are associated with rather selective white matter damage and suggest that diffuse white matter hyperintensities and increased ADC reported in infants are transient MRI changes post- hypoxia-ischemia.

White matter damage precedes that in gray matter despite similar magnetic resonance imaging changes following cerebral hypoxia-ischemia in neonatal rats.

We hypothesized that the cerebral injury produced by hypoxia-ischemia (HI) in neonatal rats would differ in white compared with gray matter as detected histologically or with magnetic resonance (MR) imaging methods. Maps of T2 and the apparent diffusion coefficient (ADC) of water were acquired in 1-week-old rats at times prior to cerebral HI (right carotid artery occlusion plus 1.5 h of hypoxia), within the last 5-10 min of HI, and 1 h or 24 h after HI. Near the end of HI, ADC decreased and T2 increased in both cortical gray and subcortical white matter within the cingulum of the HI hemisphere. One hour after HI, ADC partially recovered, but T2 remained increased and then increased further by 24 h post-HI. In contrast to the similar MR responses in white and gray matter, histological evidence for irreversible cell damage occurred in white matter earlier than in gray matter within the HI hemisphere. At 1 h post-HI, rarefied or disrupted nerve fibers and an increase in TUNEL-positive cells were observed within white matter in the cingulum, whereas neurons within the cortical gray matter appeared normal. By 24 h post-HI, damage was apparent in both white and gray matter. Thus, MR imaging detected acute tissue edema following cerebral HI in both gray and white matter but did not distinguish between the early irreversible tissue injury detected histologically in white but not gray matter in this rather severe model of neonatal encephalopathy.

Development of acute edema following cerebral hypoxia-ischemia in neonatal compared with juvenile rats using magnetic resonance imaging.

We hypothesized that the evolution of cerebral edema accompanying cerebral hypoxia-ischemia is dependent on age and that such differences would be detectable using magnetic resonance imaging methods. Thus we examined in immature and juvenile rats the relationship between hypoxic-ischemic changes in T1 and T2 and the alterations in brain water content, as assessed by differences in tissue wet-dry weights. One- and 4-wk-old rats were anesthetized and subjected to unilateral carotid artery occlusion and subsequent exposure to hypoxia (8% oxygen). T1 and T2 maps were acquired at 9.4 T, and then brain water content was measured in sham controls or in hypoxic-ischemic animals before, during, and 1 or 24 h after hypoxia-ischemia. In sham controls, T1, T2, and proton density decreased with increasing age, corresponding to an ontogenic decrease in water content. In 1-wk-old rats, increases in T1 and T2 were observed during and at 1 and 24 h after hypoxia-ischemia, corresponding to elevations in water content. In 4-wk-old rats, T1 and water content increased during and at 1 and 24 h after hypoxia-ischemia whereas T2 was not increased until 24 h after hypoxia-ischemia. Regression analysis showed that T1 correlated better with total water content than T2. In both immature and older brain, an increase in total brain water develops acutely and persists after an episode of cerebral hypoxia-ischemia, and T1 imaging detects this change better than T2. Hypoxic-ischemic changes in T2 are age dependent, reflecting other physicochemical changes of water in the tissue than water content alone.

Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat.

Whether the water channel protein AQP4 is involved in the very early cell swelling and brain oedema observed with cerebral hypoxia-ischaemia (HI) and whether this response depends on the maturity of brain were investigated by comparing regional changes in AQP4 protein expression and signal intensity on magnetic resonance (MR) images in immature and juvenile brains. Maps of T2 and the apparent diffusion coefficient (ADC) of water were acquired in 1- and 4-week-old rats at times prior to HI, within the last 5 min of HI and 1 h or 24 h afterwards. AQP4 expression assessed with Western blotting was not significantly reduced until 24 h post-HI irrespective of age. However, AQP4 immunostaining was decreased at the end of HI and at 1 h or 24 h after HI in the hemisphere ipsilateral to the occlusion with changes being similar in both age groups and coinciding well with regional reductions in ADC. IgG immunostaining to assess blood-brain barrier integrity and T2 were unchanged at early time points in 4-week old rats despite decreases in AQP4 immunostaining. Thus, at early time points there were decreases in AQP4 detected with immunostaining but not Western blotting methods. However, the good correlation between alterations in ADC and AQP4 immunostaining suggests that changes in the AQP4 are involved in some of the early changes in brain water distribution observed in hypoxia-ischemia, and supports the speculation that AQP4 is involved in the transport of water across the perivascular membranes into the vascular lumen.