Induced Lung Damage Research Articles

Lung damage analyzed by machine vision on tissue sections of mice.

The inhalation of environmental toxicants can induce lung damage. Many methods are currently available to analyze lung tissue damage and are based on empirical visual judgment; however, the accuracy of the assessments are influenced by individual differences among pathologists. Here, we establish new methods of analysis for lung tissue sections based on machine vision and verify this new automatic high-flux method with the model of mice inhaling aqueous aerosol with different concentrations of CdCl2 (0, 1, 3, 5mM 2h/day) for 7days through analyses of pulmonary porosity, mucus, pneumonia and co-localized staining. Additionally, the correlation analysis among the concentrations of CdCl2 in aqueous aerosol, the high-flux analyses and empirical visual judgment methods demonstrate the practicality of the new automatic method. The comparison between the high-flux analyses and the empirical visual judgment methods demonstrates the superiority of the new automatic method. In the future, these new automatic high-flux analyses based on machine vision could be conducive to pulmonary histology and pathology research.

The protective effect of quercetin on cyclophosphamide-Induced lung toxicity in rats

Cyclophosphamide (CYP) is an anticancer agent widely used in chemotherapy. It has been suggested that CYP causes toxicity in many organs, including the lungs and testes. Many studies have indicated that some antioxidants have possible protective effects against CYP’s side effects. This study aimed to investigate the protective effect of quercetin (QUE) on CYP-induced lung toxicity in rats using histologic and biochemical methods.In the study, 50 male Sprague-Dawley rats weighing 220–250g were used. There were 4 experimental groups and 1 control group. Group I is the control group, which was given only intragastric (i.g.) solvent (corn oil) for 7days. Group II was given i.g. corn oil for 7days as a placebo, and a single dose of intraperitoneal (i.p.) CYP (200mg/kg) was given on day 7. Groups III and IV, respectively, were given QUE in doses of 50 and 100mg/kg, dissolved in corn oil, and administered i.g. for 7days. In addition, a single dose of CYP (200mg/kg, i.p.) was administered on the 7th day of study. In Group V, a 100mg/kg dose of QUE was given to rats i.g. for 7days. On the 8th day of the experiment, all groups of rats’ blood and lung tissue samples were collected for analysis of oxidative stress parameters and histopathological examinations.In the biochemical result (although oxidative parameters were increased in favor of tissue damage) QUE administration revealed attenuated CYP toxicity in the rats ‘lungs. In histologic analysis, QUE prevented the CYP-mediated tissue damage and the increase in mast-cell densities in the rats’ lung tissues.The results of the present study have revealed that QUE provides a possible protective effect by inhibiting ROS and mast cell degranulation in induced lung damage.

Cromolyn Sodium Attenuates Paraquat-Induced Lung Injury by Modulation of Proinflammatory Cytokines.

The current study aimed to investigate the effects of Cromolyn Sodium (CS) on proinflammatory cytokines in Paraquat (PQ)-induced lung damage in rat. Animals were randomly divided into 5 groups. Group 1 and 2 received nebulized vehicle and CS (8 mg/kg) for 3 consecutive weeks, respectively. Group 3 was treated with single oral dose of PQ (40 mg/kg). Groups 4 and 5 were PQ groups which received nebulized CS (6 and 8 mg/kg/day, respectively) from 1 week before to 2 weeks after PQ administration. Finally, the animals were scarified and the changes of hydroxyproline (HP) and histology were evaluated in lung tissue. In addition, IL-1β, TNF-α and IL-8 levels were determined in serum samples. The results showed that lung HP level as well as IL-1β, TNF-α and IL-8 were significantly lower in the CS treated rats as compared to PQ group. The best response, however, was observed with the 8 mg/kg of CS as confirmed by histology findings. This study suggests that CS may prevent progression of PQ-induced lung damage by decreasing of inflammatory cytokines.

Agmatine Ameliorates Nicotine Induced Lung Injury in Rats through Decrease TGF-ß1 and Bax Immunoexpression and by Anti-oxidative Sress Pathway: Histological, Immunohistochemical and Biochemical Study

Introduction: Nicotine (NIC), the chief alkaloid in tobacco, believed to be an active agent responsible for lungassociated diseases. This protocol targeted to analyze the ameliorating effect of agmatine (AG) on NIC induced lung damage. Mateiral and methods: Forty-five adult male rats were divided into: Control group received intraperitoneal (IP) injection of distilled water, 2) NIC group recieved NIC (10 mg/kg/day) IP and 3) (NIC+AG) group treated by AG (10 mg/kg/day) orally+NIC (10 mg/kg/day) by IP injection for 9 weeks. Total serum protein, triglycerides (TGs), total cholesterol (TC), high density lipoprotein (HDL), Low density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH) and vascular cell adhesion molecule 1 (VCAM- 1) were estimated. Lung specimens were prepared and stained with H&E, Masson trichrome and immunehistochemical stains for assessment of transforming growth factor beta 1 (TGF-β1) and Bax. Morphometric study followed by statistical analysis were done. Results: NIC group showed elevation in serum levels of total protein, TC, LDL-C, TGs, MDA and VCAM-1 with evident diminishing in the serum levels of HDL-C, SOD, and GSH. Apoptosis and damage of alveolar epithelium and bronchiolar cells, marked fibrosis, inflammatory cell infiltrate and congestion of blood vessels were observed. Marked increase in the mean alveolar wall thickness, mean area% of collagen fibers deposition, mean area% of TGFβ1 immuno-expression and mean number of Bax immune positive cells while a decrease in the mean linear intercept were detected. AG co-administered with nicotine ameliorated these biochemical, histopathological and morphometric changes. Conclusion: AG ameliorates NIC induced lung damage in rats through improving the biochemical parameters and by decreasing TGF-s1 and Bax immunoexpression.

235 - Cigarette Smoke Induced Emphysema and Pulmonary Hypertension Are Triggered by Tobacco Smoke Oxidants: Attenuation by Vitamin C

Cigarette smoking causes emphysema, a fatal disease involving extensive structural and functional damage of the lung followed by pulmonary hypertension that restricts pulmonary circulation and causes right ventricular dysfunction of the heart. Using a guinea-pig model and human lung cells we show that oxidant(s) present in tobacco smoke not only cause direct oxidative damage of lung proteins, contributing to the major share of emphysematous lung injury, but are also responsible for the extensive pulmonary vascular remodelling that characterizes pulmonary hypertension. Tobacco-smoke oxidants activate the lung pro-inflammatory factor, Rtp801 which in turn stimulates nuclear-factor κB and consequent inducible nitric-oxide synthase (iNOS) mediated overproduction of nitric-oxide (NO) that contributes to lung protein nitration. However, lung-specific inhibition of iNOS with a iNOS-specific inhibitor, N6-​(1-​iminoethyl)-​L-​lysine,​ dihydrochloride (L-NIL) solely restricts the observed lung protein nitration but fails to prevent or reverse the major tobacco-smoke induced oxidative lung injury, contrary to recent reports (Cell;147(2):293-305, 2011). In fact, inhibition of pulmonary iNOS also significantly accelerates lung peri-vascular collagen deposition by up-regulating the expression of arginase I, a key enzyme associated with vascular remodelling and pulmonary hypertension. In comparison, the dietary antioxidant, ascorbate or vitamin C, can substantially prevent emphysematous lung damage by inhibiting both tobacco-smoke induced lung protein oxidation as well as activation of pulmonary Rtp801 and nitration of lung proteins, that otherwise lead to increased proteolysis of such oxidized or nitrated proteins by endogenous lung proteases, causing emphysema. Vitamin C also restricts the up-regulation of matrix-metalloproteinase-9, the major lung protease involved in the proteolysis of such modified lung proteins during tobacco-smoke induced emphysema as well as arginase I, to prevent the subsequent peri-vascular collagen deposition and medial thickening of the pulmonary vessels causing pulmonary hypertension. Thus, our findings implicate tobacco-smoke oxidant(s) as the primary etiopathogenic factor behind both the emphysematous and vascular pathogenesis of the lung associated with smoking. More importantly, it demonstrates the potential of vitamin C to accomplish holistic prevention of both these major forms of tobacco-smoke induced lung damage Reference Proc. Natl. Acad. Sci, USA,113(29):E4208-17, 2016

Hyperoxia-induced p47phox activation and ROS generation is mediated through S1P transporter Spns2, and S1P/S1P1&2 signaling axis in lung endothelium.

Hyperoxia-induced lung injury adversely affects ICU patients and neonates on ventilator assisted breathing. The underlying culprit appears to be reactive oxygen species (ROS)-induced lung damage. The major contributor of hyperoxia-induced ROS is activation of the multiprotein enzyme complex NADPH oxidase. Sphingosine-1-phosphate (S1P) signaling is known to be involved in hyperoxia-mediated ROS generation; however, the mechanism(s) of S1P-induced NADPH oxidase activation is unclear. Here, we investigated various steps in the S1P signaling pathway mediating ROS production in response to hyperoxia in lung endothelium. Of the two closely related sphingosine kinases (SphKs)1 and 2, which synthesize S1P from sphingosine, only Sphk1(-/-) mice conferred protection against hyperoxia-induced lung injury. S1P is metabolized predominantly by S1P lyase and partial deletion of Sgpl1 (Sgpl1(+/-)) in mice accentuated lung injury. Hyperoxia stimulated S1P accumulation in human lung microvascular endothelial cells (HLMVECs), and downregulation of S1P transporter spinster homolog 2 (Spns2) or S1P receptors S1P1&2, but not S1P3, using specific siRNA attenuated hyperoxia-induced p47(phox) translocation to cell periphery and ROS generation in HLMVECs. These results suggest a role for Spns2 and S1P1&2 in hyperoxia-mediated ROS generation. In addition, p47(phox) (phox:phagocyte oxidase) activation and ROS generation was also reduced by PF543, a specific SphK1 inhibitor in HLMVECs. Our data indicate a novel role for Spns2 and S1P1&2 in the activation of p47(phox) and production of ROS involved in hyperoxia-mediated lung injury in neonatal and adult mice.

The effect of diet-induced serum hypercholesterolemia on the surfactant system and the development of lung injury

Acute respiratory distress syndrome (ARDS) is a pulmonary disorder associated with alterations to the pulmonary surfactant system. Recent studies showed that supra-physiological levels of cholesterol in surfactant contribute to impaired function. Since cholesterol is incorporated into surfactant within the alveolar type II cells which derives its cholesterol from serum, it was hypothesized that serum hypercholesterolemia would predispose the host to the development of lung injury due to alterations of cholesterol content in the surfactant system.Wistar rats were randomized to a standard lab diet or a high cholesterol diet for 17–20 days. Animals were then exposed to one of three models of lung injury: i) acid aspiration ii) ventilation induced lung injury, and iii) surfactant depletion. Following physiological monitoring, lungs were lavaged to obtain and analyze the surfactant system.The physiological results showed there was no effect of the high cholesterol diet on the severity of lung injury in any of the three models of injury. There was also no effect of the diet on surfactant cholesterol composition. Rats fed a high cholesterol diet had a significant impairment in surface tension reducing capabilities of isolated surfactant compared to those fed a standard diet exposed to the surfactant depletion injury. In addition, only rats that were exposed to ventilation induced lung injury had elevated levels of surfactant associated cholesterol compared to non-injured rats.It is concluded that serum hypercholesterolemia does not predispose rats to altered surfactant cholesterol composition or to lung injury. Elevated cholesterol within surfactant may be a marker for ventilation induced lung damage.

The Protective Effects of Caffeic Acid Phenethyl Ester on Acetylsalicylic Acid-induced Lung Injury in Rats

ABSTRACTAim: We aimed to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on acetylsalicylic acid (ASA)-induced lung damage in rats in the present study. Methods: A total of 40 rats were randomly divided into five groups, with eight rats in each group—group 1: control, not receiving any medication; group 2: ASA (50 mg/kg/day); group 3: ASA (50 mg/kg/day) plus CAPE (20 μg/kg/day); group 4: ASA (100 mg/kg/day); and group 5: ASA (100 mg/kg/day) plus CAPE (20 μg/kg/day). ASA and CAPE were given via orogastric gavage for 5 days. The total oxidant status (TOS), total antioxidant capacity (TAC), oxidant stress index (OSI), and paraoxonase-1 (PON-1) activity of the blood samples and lung tissues were determined. Histopathological examinations of the lung tissues were performed by using light microscopic methods. Results: CAPE treatment significantly increased antioxidant PON-1 level both in the lung tissue and plasma (p < .05). Plasma antioxidant marker (TAC, PON-1) levels significantly increased and oxidant marker (TOS, OSI) levels significantly decreased in CAPE-treated rats (groups 3,5) compared to ASA given no-CAPE groups (group 2,4) (p < .05). Treatment with CAPE improved pulmonary interstitial inflammation and eosinophil accumulation due to ASA histopathologically. Conclusion: Eosinophil-rich inflammation and oxidative stress play important roles in ASA-induced lung toxicity, and CAPE may protect against ASA-induced lung toxicity by reduction of oxidative damage and inflammation in rats.

Mechanisms of ventilator-induced lung injury in healthy lungs.

Mechanical ventilation is an essential method of patient support, but it may induce lung damage, leading to ventilator-induced lung injury (VILI). VILI is the result of a complex interplay among various mechanical forces that act on lung structures, such as type I and II epithelial cells, endothelial cells, macrophages, peripheral airways, and the extracellular matrix (ECM), during mechanical ventilation. This article discusses ongoing research focusing on mechanisms of VILI in previously healthy lungs, such as in the perioperative period, and the development of new ventilator strategies for surgical patients. Several experimental and clinical studies have been conducted to evaluate the mechanisms of mechanotransduction in each cell type and in the ECM, as well as the role of different ventilator parameters in inducing or preventing VILI. VILI may be attenuated by reducing the tidal volume; however, the use of higher or lower levels of positive end-expiratory pressure (PEEP) and recruitment maneuvers during the perioperative period is a matter of debate. Many questions concerning the mechanisms of VILI in surgical patients remain unanswered. The optimal threshold value of each ventilator parameter to reduce VILI is also unclear. Further experimental and clinical studies are necessary to better evaluate ventilator settings during the perioperative period in different types of surgery.

Down-regulation of let-7 microRNA increased K-ras expression in lung damage induced by radon

Radon has long been recognized as a human carcinogen leading to lung cancer, but the underlying mechanisms remain obscure. Recent studies have shown that the let-7 microRNA and K-ras play an important role in the development of various cancers. However, the exact role between let-7 and K-ras in radon induced lung damage has not been explored so far. In the present study, wistar rats and human bronchial epithelial (HBE) cells were long-term exposed to radon, and then alterations in histological pathology of rat lung tissue, ROS, antioxidant enzymes activities and clonogenic formation in HBE cells, as well as changes in let-7 and K-ras expression were determined to observe the adverse effects induced by radon. The results showed that long-term exposure to radon produced severe lung damage in rats, significantly increased ROS production and clonogenic formation ratios and decreased SOD activities in HBE cells. In addition, an obvious down-regulation of let-7 and up-regulation of K-ras were also revealed both in mRNA and in protein level in lung tissue of rats and HBE cells exposed to radon. Furthermore, a significant down-regulation of K-ras was then confirmed in both let-7b-3p and let-7a-2-3p transfected HBE cells. Taken together, the present results propose an involvement of let-7 microRNA and K-ras in radon induced lung damage both in vivo and in vitro, which may thus be of potential value in early diagnosis and therapy of radon-induced lung tumorgenesis.

Effects of parecoxib on pulmonary inflammation during lung ischemia- reperfusion injury in rats

Objective To investigate the effects of parecoxib on pneumocyet apoptosis during lung ischemia- reperfusion(I/R)injury in rats. Methods Seventy- two male SD rats were randomly divided into 3 groups(n= 24 each):group sham operation; group I/R and group parecoxib.lung I/R was induced by occlusion of hilum of the right lung for 60 min followed by 120 min of reperfusion.In P group parecoxib 5 mg/kg was injected iv at 30 min before occlusion of hilum of the right lung.The rats were sacrificed at 2 h of reperfusion and then the lungs were removed for measurement of lung wet/dry weight ratio, and the percentage of neutrophil in bronchoalveolar lavage fluid (BALF) were detected. The levels of malondialdehyde(MDA) and superoxide dismutase(SOD) were measured.The tumor necrosis(TNF-α) and interleukin 1β(IL- 1β) in BALF supernatant were determined by using enzyme linked immunosorbent assay(ELISA) method. Results Parecoxib significantly attenuated the I/R- induced changes in lung.wet/dry weight ratio(6.34±0.19 vs.5.28± 0.17, P< 0.05), the levels of malondialdehyde(MDA)[(9.26±1.85) mol/L vs.(5.45±1.12) mol/ L, P< 0.05], superoxide dismutase(SOD)[(98.1±12.6) U/ml vs.(155.8±14.4) U/ml, P< 0.05]and The rumor necrosis factor-α(TNF-α)[(425.2±41.8)ng/L vs.(335.4±33.2) ng/L, P<0.05].Interleukin 1β[(178.1±22.6)ng/L vs.(105.4±15.9)ng/L, P<0.05]in group P compared with group I/R.Parecoxib ameliorated I/R- induced lung damage. Conclusion Compared with I/R group, the more attenuation of pulmonary inflammation in Parecoxib group after lung I/R injury is associated with less neutrophil activation and decrease in production of the inflammatory cytokines. Key words: Parecoxib; Reperfusion injur; Lung; Tumor necrosis factor-α; Interleukin-1

Perinatal nicotine exposure suppresses PPARγ epigenetically in lung alveolar interstitial fibroblasts.

Due to the active inhibition of the adipogenic programming, the default destiny of the developing lung mesenchyme is to acquire a myogenic phenotype. We have previously shown that perinatal nicotine exposure, by down-regulating PPARγ expression, accentuates this property, culminating in myogenic pulmonary phenotype, though the underlying mechanisms remained incompletely understood. We hypothesized that nicotine-induced PPARγ down-regulation is mediated by PPARγ promoter methylation, controlled by DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2), two known key regulators of DNA methylation. Using cultured alveolar interstitial fibroblasts and an in vivo perinatal nicotine exposure rat model, we found that PPARγ promoter methylation is strongly correlated with inhibition of PPARγ expression in the presence of nicotine. Methylation inhibitor 5-aza-2'-deoxycytidine restored the nicotine-induced down-regulation of PPARγ expression and the activation of its downstream myogenic marker fibronectin. With nicotine exposure, a specific region of PPARγ promoter was significantly enriched with antibodies against chromatin repressive markers H3K9me3 and H3K27me3, dose-dependently. Similar data were observed with antibodies against DNA methylation regulatory factors DNMT1 and MeCP2. The knock down of DNMT1 and MeCP2 abolished nicotine-mediated increases in DNMT1 and MeCP2 protein levels, and PPARγ promoter methylation, restoring nicotine-induced down regulation of PPARγ and upregulation of the myogenic protein, fibronectin. The nicotine-induced alterations in DNA methylation modulators DNMT1 and MeCP2, PPARγ promoter methylation, and its down-stream targets, were also validated in perinatally nicotine exposed rat lung tissue. These data provide novel mechanistic insights into nicotine-induced epigenetic silencing of PPARγ that could be exploited to design novel targeted molecular interventions against the smoke exposed lung injury in general and perinatal nicotine exposure induced lung damage in particular.

PSTK is a novel gene associated with early lung injury in Paraquat Poisoning

AimsParaquat Poisoning (PQ) can cause illness and death, and its main causes of mortality are acute respiratory failure and lung fibrosis. Early recognition of this condition and early treatment are vital. Thus, it is of importance to target the key genes controlling pathogenesis in the early stage of PQ. Main methodsC57BL/6 mice were used for Paraquat intragastric administration as a model of PQ. Following a gene chip-based screening, the change of gene expression in the lung was further validated by bioinformatic analyses, co-expression network construction and real-time RT-PCR, Western blot and immunofluorescence assays. Key findings2287 genes with differential expression were identified at the very early stage of PQ. From these, 76 genes that were linked to mitochondrion function were further pursued. Among these genes, PSTK was a phosphorylase kinase which serves a protective role in oxidative stress lung damage. PSTK was the central gene in a 30-gene network that is important for mitochondrial complex I assembly, mitochondrial apoptosis and mitochondrial fatty acid beta-oxidation, suggesting that they could conceivably be related to the pathogenesis of PQ induced lung damage. Lastly, we confirmed that PSTK was lowered in rodent lungs following PQ. SignificancePSTK emerges as a central gene in a network of mitochondrial function genes in PQ exposed mice. The functional role of PSTK in PQ induced lung injury warrants further examination.

Blueberry anthocyanins-enriched extracts attenuate the cyclophosphamide-induced lung toxicity

The influence of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced lung damage was investigated. BAE (20 and 80mg/kg/d) were orally dosed to rats 7d both before and after CTX administration (100mg/kg, intraperitoneal injection, single dose). The results showed CTX treatment induced obvious pathological pulmonary injury with raised injury score and lung/body weight ratio. In CTX group, the activity of lysosomal proteases, lung permeability and the number of neutrophil infiltrates all elevated. On the other hand, claudin-4 and zonula occluden-1 protein levels decreased. And also changes of oxidative stress and inflammatory cytokines parameters together with nuclear factor-κB activation were shown. Improvement of all above-mentioned physiological and biochemical parameters was exhibited in BAE groups, with a dose-dependent manner. In conclusion, BAE attenuate the CTX-induced lung toxicity, antioxidant and anti-inflammatory characteristics are involved in the protective mechanism of BAE.

Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage.

Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.

Macrophage Migration Inhibitory Factor Is a Novel Determinant of Cigarette Smoke–Induced Lung Damage

Cigarette smoke (CS) is the most common cause of chronic obstructive pulmonary diseases (COPD), including emphysema. CS exposure impacts all cell types within the airways and lung parenchyma, causing alveolar tissue destruction through four mechanisms: (1) oxidative stress; (2) inflammation; (3) protease-induced degradation of the extracellular matrix; and (4) enhanced alveolar epithelial and endothelial cell (EC) apoptosis. Studies in human pulmonary ECs demonstrate that macrophage migration inhibitory factor (MIF) antagonizes CS-induced apoptosis. Here, we used human microvascular ECs, an animal model of emphysema (mice challenged with chronic CS), and patient serum samples to address both the capacity of CS to alter MIF expression and the effects of MIF on disease severity. We demonstrate significantly reduced serum MIF levels in patients with COPD. In the murine model, chronic CS exposure resulted in decreased MIF mRNA and protein expression in the intact lung. MIF deficiency (Mif(-/-)) potentiated the toxicity of CS exposure in vivo via increased apoptosis of ECs, resulting in enhanced CS-induced tissue remodeling. This was linked to MIF's capacity to protect against double-stranded DNA damage and suppress p53 expression. Taken together, MIF appears to antagonize CS-induced toxicity in the lung and resultant emphysematous tissue remodeling by suppressing EC DNA damage and controlling p53-mediated apoptosis, highlighting a critical role of MIF in EC homeostasis within the lung.

Comparative Study between Intravenous and Intraperitoneal Stem Cell Therapy in Amiodarone Induced Lung Injury in Rat.

Background and Objectives:The fibrosing form of lung injury (occupational, environmental, infective or drug induced) is associated with significant morbidity and mortality. Amiodarone (AM), often prescribed for control of arrhythmias is considered a potential cause. No effective treatment was confirmed, except lung transplantation. Intravenous (IV) stem cell therapy may produce pulmonary emboli or infarctions. Despite being commonly used in clinical practice, the intraperitoneal (IP.) route has been rarely used for cell delivery. The present study aimed at investigating and comparing the possible effect of IP stem cell therapy (SCT) on pulmonary toxicity versus the intravenous route in a rat model of amiodarone induced lung damage.Methods and Results:36 adult male albino rats were divided into 4 groups. Rats of AM group were given 30 mg/kg daily orally for 4 weeks. Rats of IV SCT group were injected with stem cells in the tail vein. Rats of IP SCT group received IP cell therapy. Histological, histochemical, immunohistochemical and morphometric studies were performed. Obstructed bronchioles, overdistended alveoli, reduced type I pneumocytes, increased thickness of alveolar septa and vessels wall besides increased area% of collagen fibers regressed in response to IV and IP SCT. The improvement was more obvious in IV group. The area% of Prussion blue +ve and CD105 +ve cells was significantly higher in IV group.Conclusions:Cord blood MSC therapy proved definite amelioration of lung injury ending in fibrosis. The effect of IP SCT was slightly inferior to that of IV SCT, which may be overwhelmed by repeated IP injection.

TH‐E‐BRF‐04: Characterizing the Response of Texture‐Based CT Image Features for Quantification of Radiation‐Induced Normal Lung Damage

Purpose:Radiation induced lung damage (RILD) is an important dose‐limiting toxicity for patients treated with radiation therapy. Scoring systems for RILD are subjective and limit our ability to find robust predictors of toxicity. We investigate the dose and time‐related response for texture‐based lung CT image features that serve as potential quantitative measures of RILD.Methods:Pre‐ and post‐RT diagnostic imaging studies were collected for retrospective analysis of 21 patients treated with photon or proton radiotherapy for NSCLC. Total lung and selected isodose contours (0–5, 5–15, 15–25Gy, etc.) were deformably registered from the treatment planning scan to the pre‐RT and available follow‐up CT studies for each patient. A CT image analysis framework was utilized to extract 3698 unique texture‐based features (including co‐occurrence and run length matrices) for each region of interest defined by the isodose contours and the total lung volume. Linear mixed models were fit to determine the relationship between feature change (relative to pre‐RT), planned dose and time post‐RT.Results:Seventy‐three follow‐up CT scans from 21 patients (median: 3 scans/patient) were analyzed to describe CT image feature change. At the p=0.05 level, dose affected feature change in 2706 (73.1%) of the available features. Similarly, time affected feature change in 408 (11.0%) of the available features. Both dose and time were significant predictors of feature change in a total of 231 (6.2%) of the extracted image features.Conclusion:Characterizing the dose and time‐related response of a large number of texture‐based CT image features is the first step toward identifying objective measures of lung toxicity necessary for assessment and prediction of RILD. There is evidence that numerous features are sensitive to both the radiation dose and time after RT. Beyond characterizing feature response, further investigation is warranted to determine the utility of these features as surrogates of clinically significant lung injury.

Differential function of IL-17A in cigarette smoke induced lung damage

Smoking is the main risk factor for the chronic obstructive pulmonary disease (COPD). A recent study demonstrated by quantitative microcomputed tomography (µCT) that IL-17A-deficient mice exposed to cigarette smoke are protected from increases in lung volume and decreased lung density. This suggests that Th-17/IL-17-dependent immune mechanisms mediate smoke-induced lung damage, such as the development of emphysema. Here, we demonstrate a more complex role of IL-17A in the development of lung damage in mice chronically exposed to smoke. Physiologically relevant pulmonary function showed that IL-17A deficient mice were per se not protected from smoke-induced emphysematous disease. Respiratory compliance was increased in IL-17-deficient mice after smoke exposure, even though IL-17-deficient mice were partially protected from smoke-induced changes in the total lung capacity and hysteresis. Histology and morphometry showed that smoke-exposure results in loss of lung structure in IL-17-deficient mice. These results suggest that, in the present disease model, IL-17A rather has a protective than a deleterious role in smoke-induced loss of lung function.

Differential function of IL-17A in cigarette smoke induced lung damage

Differential function of IL-17A in cigarette smoke induced lung damage