Morphological Changes In Lungs Research Articles

Precapillary pulmonary hypertension leads to reversible bronchial hyperreactivity in rats

ABSTRACTCongenital heart disease with left-to-right shunt may lead to precapillary pulmonary hypertension (PREPHT) with potential lung function impairment. The authors investigated the effects of PREPHT on lung responsiveness in a rat model of PREPHT by creating and repairing an abdominal aortocaval shunt (ACS). Rats were studied 4 weeks after the induction of ACS, and 4 weeks after its surgical repair. Control rats underwent sham surgery. To assess bronchial hyperreactivity, airway resistance (Raw) was measured at baseline and after increasing doses of methacholine. Raw was estimated by model fitting of the mechanical impedance of the respiratory system generated by forced oscillation technique. Lung morphological changes were assessed by histology. The prolonged presence of the ACS led to only minor changes in the basal respiratory mechanics, whereas it induced marked bronchial hyperreactivity, the methacholine-induced elevations in Raw being 49% ± 5% before and 232% ± 32% (P <.001) after ACS. These alterations were not associated with any changes in lung histology and were completely reversible on closure of the shunt. These results suggest that the induction of chronic increases in pulmonary blood flow and pressure causes reversible bronchial hyperreactivity. This may be consequent to the altered mechanical interdependence between the pulmonary vasculature and the respiratory tract.

609 A combined high temporal and high spatial resolution 3 Tesla MR imaging protocol for the assessment of breast lesions: initial results

Chest imaging is essential in the assessment of respiratory disease in cystic fibrosis (CF). High-resolution computed tomography (HRCT) can detect progressive lung disease but involves significant delivered dose of ionizing radiation. Magnetic resonance imaging (MRI) is radiation-free but is rarely used in CF. Based on the limited information on the potential interest of chest MRI in CF pediatric patients, the aims of our study were: 1) to evaluate and compare the reproducibility of HRCT and MRI scores; and 2) to evaluate the agreement between HRCT and MRI scores using both Helbich and Eichinger scores.In this prospective study, CF children who were having a HRCT for their routine assessment were proposed to perform a chest MRI the same day. 17 patients were included (median age 12.7 years). Two radiologists scored independently HRCT (Helbich score) and MRI (Helbich and Eichinger scores); and established a consensus score. Concordance was assessed using the Intraclass Correlation Coefficient (ICC); and the inter-observer reproducibility between methods was compared using Fisher's Z test for dependent observations.Concordance between readers was almost perfect for HRCT score (ICC = 96%) and MRI-Eichinger score (84%), and substantial for MRI-Helbich score (68%). Correlation was strong between HRCT and MRI (r = 0.86 and 0.91 for HRCT and respectively MRI-Eichinger and MRI-Helbich scores) and the concordance almost perfect and substantial (ICC = 86% and 78% for HRCT and respectively MRI-Eichinger and MRI-Helbich scores).We showed that, in CF children, MRI could adequately visualize lung morphologic changes when compared with the “gold-standard” HRCT. Regarding the potential cancer risks from associated ionizing radiation with HRCT, these results lead us to propose larger intervals of time between two lung HRCTs with realization of lung MRI in the meantime.

The establishment of pulmonary acute lung injury model in rats

Objective To establish pulmonary acute lung injury(ALI)model in rats.Methods ALI model was induced in rats by intratracheal Escherichia coli injection[3 ml/kg,O111B4,(4.0～6.0)×1012 CFU/L].Mechanical ventilation was applied 12,24,36,48 and 72 h after Escherichia coli injection,PaO_2/FiO_2 and dynamic compliance were recorded,and the normal control group was also subjected to mechanical ventilation.After the experiment,lungs were fixed with formalin to perform pathological examination.Results At 12,24,36,48 and 72 h,the PaO_2/FiO_2 were(30.71±7.95)kPa,(21.66±5.34)kPa,(21.09±4.75)kPa,(25.01±8.78)kPa and(33.82±8.02)kPa,respectively,which were significantly lower than that in the normal control group(63.82±3.03)kPa(P＜0.01).At 12,24,36,48 and 72 h,the Cdyn were(4.23±0.13)ml/(kg·kPa),(4.19±0.96)ml/(kg·kPa),(4.28±0.69)ml/(kg·kPa),(4.44±0.62)ml/(kg·kPa)and(4.58±0.35)ml/(kg·kPa)respectively,which were significantly lower than that in the normal control group(8.16±0.78)mL/(kg·kPa)(P＜0.01).At 12,24,36,48 and 72,the percentage of ALI was 71.4%,100.0%,100.0%,83.3%and 57.1%respectively,and the percentage of ARDS was 28.6%,85.7%,83.3%,66.7%,14.3%respectively.As for pathological examinations,predominance of alveolar collapse,fibrinous exudates,alveolar wall edema and neutrophil recruitment into the alveolar space was observed.Hyaline membrane formation was found.At 72 h,inflammation was relieved.Conclusion We successfully established pulmonary ALI/ARDS model in rats induced by intratracheal Escherichia coli injection,and acquired some useful information by observing the lung function and morphological changes at different time points. Key words: Acute lung injury; Escherichia coli; Animal model

Environmental Tobacco Smoke Exposure and Airway Hyperresponsiveness

Environmental tobacco smoke (ETS) exposure is a common health concern despite legislation to limit its presence, especially in public environments. ETS exposure is associated with changes in lung development and morphology, airway hyperresponsiveness and obstruction and development of asthma and its increased severity. However these effects of ETS exposure are not universally supported. Clinical data as well as studies in laboratory animals report ETS exposure may even attenuate airway hyperresponsiveness (AHR). Therefore, we lack complete understanding of ETS effects on pulmonary function as well as its mechanism of action. Disparate clinical and laboratory reports likely result from variables of ETS exposure, degrees of atopy and mechanisms of sensitization. The present review addresses the effects of ETS on AHR reported in humans and animal models. ETS role as an adjuvant to AHR as well as it contribution to development of antigenic tolerance is also reviewed. Possible neurogenic, cellular and intracellular mechanisms of ETS-induced ARH are proposed based on the existing literature. Enhanced understanding of the effects and mechanism of ETS will enhance therapy strategies in treatment of ARH and related disease such as COPD as well as enhancing public presentation of convincing evidence to avoid ETS.

Protective effects of safflor yellow on acute lung injury induced by oleic acid in rats

Objective To investigate the inhibition of safflor yellow on acute lung injury induced by oleic kg-1 mixed with 0.4% bovine serum albumin,while the drugs or normal saline were. injected 30 minutes before-hand. The experiment was made in the Animal Lab and the Pharmacology Lab of Beijing Anzhen Hospital. One hundred and nine healthy Wistar rats were randomly divided into six groups: normal control group (n = 16), mod-of oleic acid injection. The lung morphological changes were observed by optical microscopy and electron mi-croscopy, plasma IL-1β and IL-6 levels were determined by ELISA, lung index, A index and B index were mea-sured. The data were expressed as (x±s) and analyzed by One-Way ANOVA after normality and homogeneity-of-variance tests by SPSS 10.0 software. A P value less than 0.05 indicated statistical significance. Results L-1], the lung index, A index, B index as well as the plasma levels of IL-1β and IL-6 [(56.8±4.5), (20.0± 0.01 or P < 0.05), and tho lung morphological changes were obvious, such as: alveolar septum widened, edema existing in interstitial spaces, etc. In the three SY groups and the anisedamine group, the lung morphological changes were ameliorated; the three indexes and the levels of IL-1β and IL-6 were significantly reduced (P < 0.01 or P < 0.05), compared with the model group. Conclusions SY significantly inhibited oleic acid induced lung inflammation in rats. Key words: Safllor yellow; Acute lung injury; Oleic acid; Inflammation

Chinese green tea ameliorates lung injury in cigarette smoke-exposed rats

Epigallocatechin-3-gallate (EGCG), which has been shown to have potent antioxidant effect, comprises 80% of catechins in Chinese green tea. This study was to investigate whether cigarette smoke (CS) exposure would induce lung morphological changes and oxidative stress in the CS-exposed rat model, and whether Chinese green tea (Lung Chen tea with EGCG as its main active ingredient) consumption would alter oxidative stress in sera and lung leading to protection of CS-induced lung damage. Sprague-Dawley rats were randomly divided into four groups, i.e. sham air (SA), 4% CS, 2% Lung Chen tea plus SA or 4% CS. Exposure to SA or 4% CS was performed for 1h/day for 56 days in ventilated smoking chambers. Sera and lung tissues were collected 24h after last CS exposure for histology and all biochemical assays. Airspace enlargement and goblet cell hyperplasia were observed after 56-day CS exposure alone, which were abolished in the presence of green tea consumption. Serum 8-isoprostane level was significantly elevated (p<0.01) as well as lung superoxide dismutase (SOD) and catalase activities in CS-exposed rats compared to SA-exposed rats (p<0.05), which returned to the levels of SA-exposed rats after Chinese green tea consumption. These results indicate that increased levels of systemic oxidative stress after CS exposure play an important role in the induction of lung damage. Chinese green tea may have the ability to suppress CS-induced oxidative stress that leads to protection of lung injury.

Pulmonary Changes in Preterm Neonates with Hyaline Membrane Disease (a Clinicomorphological Study)

Objective: to reveal lung morphological changes in preterm neonatal infants with hyaline membrane disease (HMD) in the use of exogenous surfactants and artificial ventilation. Materials and methods. Case histories and autopsy protocols were analyzed in 90 preterm neonates who had died from severe respiratory failure. All the neonates were divided into 4 groups: 1) 20 (22.2%) infants who had received the exogenous surfactant Curosurf in the combined therapy of HMD; 2) 19 (21.1%) babies with HMD who had taken Surfactant BL; 3) 25 (27.8%) surfactant-untreated infants who had died from HMD; 4) 26 (28.9%) very preterm neonates with extremely low birth weight who had died within the first hour of life. The lungs were histologically and morphometrically examined. Results. The study demonstrated the specific course of HMD when exogenous surfactants and artificial ventilation were used. The contributors to the development of the disease are intranatal amniotic fluid aspiration and intranatal fetal hypoxia. Conclusion. Artificial ventilation and the use of exogenous surfactants do not block the generation of hyaline membranes. The latter differ in formation time, form, and location. The differences in a cell response to hyaline membranes were found in the neonatal infants receiving exogenous surfactants. The characteristic morphological signs of the disease for all the neonates enrolled in the study are alveolar and bronchial epithelial damages and microcirculatory disorders. Key words: preterm neonatal infants, hyaline membrane disease, exogenous surfactants, artificial ventilation, histology, morphometry.

Effects of acute hypervolemic hemodilution with hydroxyethyl starch 130/0.4 on the lung in a rabbit model of sepsis

To investigate the effects of acute hypervolemic hemodilution (AHH) with hydroxyethyl starch (HES) 130/0.4 on the lung in a rabbit model of sepsis and their possible mechanism. Thirty healthy New Zealand rabbits were randomly divided into three groups (n=10 each): group sham operation (C), group sepsis model (E) and group AHH. Sepsis model was reproduced with modified colon ascendens stent peritonitis (CASP). In group C laparotomy was done but without puncturing the colon. At 4 hours after CASP, AHH was carried out intravenous infusion of 6% HES 130/0.4 20 ml/kg at 20 ml/min. Lactated Ringer solution was infused at 10 ml kg (-1) h (-1) in all three groups during the experiment. The animals breathed spontaneously during the experiment. A catheter was introduced into the right carotid artery for blood sampling, and it was connected to a pressure transducer for continuous mean arterial pressure (MAP) and heart rate (HR) monitoring. At 4 hours and 8 hours after CASP, a median abdominal incision was made and photographic documentation of abdominal situs was made. At the same time arterial blood samples were drawn at 4 hours and 8 hours after CASP for blood gas analysis and determination of hemoglobin (Hb) and hematocrit (Hct). The plasma component was separated and tumor necrosis factor-alpha (TNF-alpha) was measured. Respiratory rate and urinary output were record. The rabbits were sacrificed at 8 hours after CASP. The right lungs were immediately removed for determination of total protein concentration in broncho-alveolar lavage fluid (BALF). The wet/dry (W/D) lung weight rate were calculated. The sections of lung were stained with hematoxylin and eosin for light microscopic examination and the injury score was recorded. (1)MAP declined gradually and HR tended to accelerate during the course of the experiment in group E, but no significant differences were found in both group C and group AHH. (2)After AHH, the Hb and Hct decreased by 20% in group AHH. In group E, arterial oxygen saturation (SaO(2)), arterial partial pressure of oxygen (PaO(2)), arterial partial pressure of carbon dioxide (PaCO(2)) and pH decreased significantly at 8 hours after CASP compared with group C (all P<0.05). (3)TNF-alpha concentration in plasma was higher in group E and group AHH than in group C at 4 hours after CASP (both P<0.05). At 8 hours TNF-alpha concentration was increased in group E compared with group C (P<0.05), but there was no significant difference between group C and group AHH. (4)In group E, score of morphological changes in lung was significantly increased compared with group AHH (6.9+/-1.4 vs. 11.2+/-1.7, P<0.05). AHH with HES 130/0.4 can protect the lungs from sepsis. Inhibition of proinflammatory cytokines may be involved in the mechanism.

CT-scan lung morphology predicts the response to a recruitment maneuver in acute respiratory distress syndrome patients

CT-scan lung morphology (lobar or nonlobar) is the main determinant of positive end-expiratory pressure (PEEP) response. Repartition of gas and tissue probably influences the response to a recruitment maneuver (RM), but to date there is no proof. The aim of this study was to assess RM-induced changes in lung morphology and gas exchange during and after RM in acute respiratory distress syndrome (ARDS) patients.

ADMINISTRATION OF EXOGENOUS FRACTALKINE, A CX3C CHEMOKINE, IS CAPABLE OF MODULATING INFLAMMATORY RESPONSE IN CECAL LIGATION AND PUNCTURE-INDUCED SEPSIS

Fractalkine (FTK) is a unique member of the CX3C chemokine family by acting through the CX3CR1 receptor. Membrane-bound FTK acts like an adhesion molecule, whereas soluble FTK (sFTK) acts as a classic chemokine ligand. Whether this chemokine plays a role in sepsis is still not clear. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that FTK levels were elevated in plasma 24 h after CLP. Reverse transcription-polymerase chain reaction results showed that FTK messenger RNA levels were upregulated, whereas CX3CR1 messenger RNA levels were downregulated in lungs after CLP procedure. To study the role of FTK in lung injury during sepsis, we injected exogenous sFTK into the mice before the CLP procedure. We found that plasma FTK levels were further elevated by sFTK. Mice that were injected with FTK had a lower myeloperoxidase activity in lungs compared with the CLP group. Furthermore, macrophage inflammatory protein 2, IL-1beta, and IL-6 levels in lungs were reduced after the injection of FTK. Treatment with sFTK also attenuated lung morphological changes in histological sections. To find out whether sFTK had an effect on leukocyte rolling and adherence, intravital microscope was used. Results showed that sFTK significantly attenuated leukocyte adhesion but had little effect on leukocyte rolling in mesenteric microcirculation. Taken together, our findings suggest that FTK may be a novel chemokine that modulates neutrophil infiltration and chemokine and cytokine production during sepsis.

Lung Development in the Holtzman Rat is Adversely Affected by Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that elicits a wide range of toxic effects on the developing organism. In this study, we demonstrate that the fetal and neonatal rat lung contains a responsive Ahr-signaling pathway which upon activation by a gestational exposure to TCDD, leads to altered lung development. Pregnant Holtzman rats received a single oral dose of TCDD (1.5 or 6 microg/kg) on gestation day (GD) 10 or a vehicle control with fetal and neonatal analysis occurring on GD20 or postnatal day (PND) 7. Components of the aryl hydrocarbon receptor (Ahr) signaling pathway (Ahr and Arnt) were identified in the fetal and neonatal lung tissue through the use of real-time PCR and immunohistochemical staining at both time points. Additionally, the Ahr-signaling pathway was found to be responsive to the gestational TCDD exposure as demonstrated by the induction of Cyp1a1, Cyp1b1, and Ahrr in both fetal and neonatal lung tissue. Morphometric analysis of GD20 and PND7 fixed lung tissue sections revealed that treated pups had significant decreases in total airspace area while having significantly wider tissue septa separating the airspaces as well as a decreased dry lung weight to body weight ratio when compared with controls; indicative of lung immaturity and hypoplasia. Finally, the assessment of respiratory mechanics on PND7 pups revealed functionally different pressure-volume curves in TCDD-exposed pups when compared with control animals. Together, these data identify a responsive Ahr-signaling pathway in the developing lung which may be related to the pulmonary immaturity and hypoplasia induced by TCDD and demonstrates that gestational exposure to TCDD alters lung development in such a manner that changes in lung morphology are associated with functional differences in respiratory mechanics.

HIF1α Is Essential for Normal Intrauterine Differentiation of Alveolar Epithelium and Surfactant Production in the Newborn Lung of Mice

Neonatal respiratory distress syndrome (RDS) is mainly the result of perturbation in surfactant production and is a common complication seen in premature infants. Normal fetal lung development and alveolar cell differentiation is regulated by a network of transcription factors. Functional loss of any of these factors will alter the developmental program and impact surfactant production and normal gas exchange. During development, the fetus is exposed to varying oxygen concentrations and must be able to quickly adapt to these changes in order to survive. Hypoxia-inducible factor 1alpha (HIF1alpha) is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension and is essential for normal development. Its role in lung maturation is not well defined and to address this knowledge gap, a lung-specific HIF1alpha knock-out model has been developed. Loss of HIF1alpha early in lung development leads to pups that die within hours of parturition, exhibiting symptoms similar to RDS. Lungs from these pups display impaired alveolar epithelial differentiation and an almost complete loss of surfactant protein expression. Ultrastructural analysis of lungs from HIF1alpha deletion pups had high levels of glycogen, aberrant septal development, and decreased expression of several factors necessary for proper lung development, including HIF2alpha, beta-catenin, and vascular endothelial growth factor. These results suggest that HIF1alpha is essential for proper lung maturation and alteration in its normal signaling during premature delivery might explain the pathophysiology of neonatal RDS.

Ventilation of the Very Immature Lung In Utero Induces Injury and BPD-Like Changes in Lung Structure in Fetal Sheep

Preterm infants are at high risk of developing ventilator-induced lung injury (VILI), which contributes to bronchopulmonary dysplasia. To investigate causes of VILI, we have developed an animal model of in utero ventilation (IUV). Our aim was to characterize the effects of IUV on the very immature lung, in the absence of nonventilatory factors that could contribute to lung pathology. Fetal sheep were ventilated in utero at 110 d gestation for 1, 6, or 12 h (two groups; n = 5 each). Lung tissue was collected at 12 h after initiating IUV in the 1, 6, and one 12 h IUV groups. Lung liquid was replaced in the second 12 h IUV group and tissues collected at 117 d. Operated, nonventilated 110 and 117 d fetuses were controls. IUV reduced secondary septal crest densities, simplified distal airsacs, caused abnormal collagen and elastin deposition, and stimulated myofibroblast differentiation and cellular proliferation. IUV causes VILI in very immature lungs in the absence of other complicating factors and reproduces bronchopulmonary dysplasia -like changes in lung morphology. IUV offers a novel method for dissociating VILI from other iatrogenic factors that could contribute to altered lung development caused by VILI.

Morphological Assessment of the Safety of Alveolar Opening

Objective: The safety of an alveolar mobilization technique was morphologically evaluated. Materials and methods. Experiments were made on 46 non-inbred albino male rats weighing 280—320 g. Thiopental sodium (15—20 mg/kg animal weight) was intraperitoneally injected for anesthesia. A TSE Animal Respirator was employed for 30—180 minutes. In the first experimental animal group, the ventilation parameters were as follows: air flow 0.4—0.5 l/min; respiration rate 60 per min; tidal volume 1—5 ml; PEEP (during alveolar opening) 40 cm H2O (40 seconds); PEEP (after recruitment) 10 cm H2O (20 minutes). Recruitment was carried out at 20-minute intervals for 1—3 hours. Experimental Group 2 animals underwent artificial ventilation (AV) with the following ventilation parameters: air flow 0.4—0.5 l/min; respiration rate 60 per min; tidal volume 1—5 ml; PEEP (during alveolar opening) 20 cm H2O (20 seconds); PEEP (after recruitment) 10 cm H2O (20 minutes). The control animals had AV with the ventilation parameters: air flow 0.4—0.5 l/min; respiration rate 60 per min; tidal volume 1—5 ml; PEEP 0 cm H2O. Lung pieces were fixed in 10% neutral formalin solution and embedded in paraffin. The histological specimens were stained with hematoxylin and eosin; the Schick test was carried out. Results. Histological study of the lung from the experimental group animals has shown dilated alveoli and bronchioli. The increased alveolar volume at a high air flow and PEEP leads to air-blood barrier damage, alveolar septal infiltration with leukocytes, neutrophils, and macrophages, and to the development of interstitial and alveolar edema. Lung morphological changes were less pronounced in the animals from the second experimental group. Conclusion. The alveolar opening technique improves gas exchange parameters, as evidenced by oxygen utilization. The high PEEP values are attended by more significant lung morphological changes. Key words: alveolar recruitment, open lungs, PEEP.

Aspiration-Induced Acute Lung Injury: Experimental Morphological Study

Objective: to reveal early lung morphological changes after acidin-pepsin aspiration (a combination of hydrochloric acid and proteolytic enzyme). Material and methods. An experiment was made on 30 non-inbred albino male rats whose trachea acidin-pepsin solution (pH 1.2) was administered into. The experiment lasted 1 to 24 hours. Lung histological specimens were stained with hematoxylin and eosin. Results. After an hour of surgery, all the animals developed interstitial edema, had the desquamated bronchial epithelium, segmented leukocytic infiltration of alveolar septa, hemorrhages, and sludges. Conclusion. Acidin-pepsin aspiration leads to the development of acute lung injury verified by morphological studies. Key words: aspiration, acute lung lesion.

Mechanisms of airway hyper-responsiveness after coronary ischemia

We explored the consequences of myocardial ischemia (MI) on the lung responsiveness and identified the pathophysiological mechanisms involved. Airway resistance (R(aw)) was identified from the respiratory system input impedance (Z(rs)) in rats. Z(rs) was determined under baseline conditions, and following iv boluses of 20 and 30 microg/kg serotonin. MI was then induced in the animals in Group I by ligating the left-interventricular coronary artery, while rats in Group C underwent sham surgery. Four weeks later, baseline Z(rs) and its changes following serotonin administration were reassessed. Lung morphological changes were assessed by histology, and alpha smooth muscle actin cells (alpha-SMA) were identified. MI induced no changes in baseline R(aw) but led to bronchial hyper-reactivity (BHR) with 2.7+/-0.5-times (p<0.05) greater responses in R(aw) to 30 microg/kg serotonin. Perivascular edema and alpha-SMA cell proliferation were observed after MI. The development of BHR following MI is a consequence of the expression of alpha-SMA, while the geometrical alterations caused by the pulmonary vascular engorgement have smaller impact.

Small Molecular Inhibitor of Transforming Growth Factor-β Protects Against Development of Radiation-Induced Lung Injury

To determine whether an anti-transforming growth factor-beta (TGF-beta) type 1 receptor inhibitor (SM16) can prevent radiation-induced lung injury. One fraction of 28 Gy or sham radiotherapy (RT) was administered to the right hemithorax of Sprague-Dawley rats. SM16 was administered in the rat chow (0.07 g/kg or 0.15 g/kg) beginning 7 days before RT. The rats were divided into eight groups: group 1, control chow; group 2, SM16, 0.07 g/kg; group 3, SM16, 0.15 g/kg; group 4, RT plus control chow; group 5, RT plus SM16, 0.07 g/kg; group 6, RT plus SM16, 0.15 g/kg; group 7, RT plus 3 weeks of SM16 0.07 g/kg followed by control chow; and group 8, RT plus 3 weeks of SM16 0.15 g/kg followed by control chow. The breathing frequencies, presence of inflammation/fibrosis, activation of macrophages, and expression/activation of TGF-beta were assessed. The breathing frequencies in the RT plus SM16 0.15 g/kg were significantly lower than the RT plus control chow from Weeks 10-22 (p <0.05). The breathing frequencies in the RT plus SM16 0.07 g/kg group were significantly lower only at Weeks 10, 14, and 20. At 26 weeks after RT, the RT plus SM16 0.15 g/kg group experienced a significant decrease in lung fibrosis (p = 0.016), inflammatory response (p = 0.006), and TGF-beta1 activity (p = 0.011). No significant reduction was found in these measures of lung injury in the group that received SM16 0.7 g/kg nor for the short-course (3 weeks) SM16 at either dose level. SM16 at a dose of 0.15 g/kg reduced functional lung damage, morphologic changes, inflammatory response, and activation of TGF-beta at 26 weeks after RT. The data suggest a dose response and also suggest the superiority of long-term vs. short-term dosing.

Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2

The importance of HER2/HER3 signaling in decreasing the effects of lung injury was recently demonstrated. Transgenic mice unable to signal through HER2/HER3 had significantly less bleomycin-induced pulmonary fibrosis and showed a survival benefit. Based on these data, we hypothesized that pharmacological blockade of HER2/HER3 in vivo in wild-type mice would have the same beneficial effects. We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2/HER3 signaling. The administration of 2C4 before injury decreased the effects of bleomycin at days 15 and 21 after injury. HER2/HER3 blockade resulted in less collagen deposition (362.8 +/- 37.9 compared with 610.5 +/- 27.1 microg/mg; P = 0.03) and less lung morphological changes (injury score of 1.99 +/- 1.55 vs. 3.90 +/- 0.76; P < 0.04). In addition, HER2/HER3 blockade resulted in a significant survival advantage with 50% vs. 25% survival at 30 days (P = 0.04). These results confirm that HER2 signaling can be pharmacologically targeted to reduce lung fibrosis and remodeling after injury.

Adrenomedullin and Adrenomedullin Binding Protein-1 Prevent Acute Lung Injury after Gut Ischemia-Reperfusion

Ischemic bowel remains a critical problem, resulting in up to 80% mortality. Acute lung injury, a common complication after intestinal ischemia/reperfusion (I/R), might be responsible for such a high mortality rate. Our previous studies have shown that administration of a novel vasoactive peptide adrenomedullin (AM) and its binding protein (AMBP-1) reduces the systemic inflammatory response in rat models of both hemorrhage and sepsis. It remains unknown whether administration of AM/AMBP-1 has any protective effects on intestinal I/R-induced acute lung injury. We hypothesized that administration of AM/AMBP-1 after intestinal I/R prevents acute lung injury through downregulation of proinflammatory cytokines. Intestinal I/R was induced by placing a microvascular clip across superior mesenteric artery (SMA) for 90 minutes in adult male Sprague-Dawley rats (275 to 325 g). On release of the SMA clamp, the animals were treated with either AM (12 mug/kg body weight) in combination with AMBP-1 (40 microg/kg body weight) or vehicle (1 mL normal saline) during a period of 30 minutes through a femoral vein catheter. Lung samples were collected at 4 hours after treatment or sham operation. Lung injury was assessed by examining lung water content, morphologic changes, and granulocyte myeloperoxidase activity. Tumor necrosis factor-alpha and interleukin-6 gene expression and their protein levels in the lungs were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In additional groups of animals, AM/AMBP-1 or vehicle was administered at 1 hour after onset of reperfusion. Lung histology was examined at 3 hours after treatment. Intestinal I/R induced considerable lung injury, as characterized by lung edema, histopathologic changes, increased myeloperoxidase activity, and proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) levels in the lungs. Administration of AM/AMBP-1 after ischemia mitigated lung injury and dramatically downregulated proinflammatory cytokines. Lung injury was also ameliorated by delayed AM/AMBP-1 treatment as evidenced by improvement in lung histology. AM/AMBP-1 can be developed as a novel treatment to attenuate acute lung injury after an episode of gut ischemia. The protective effect of AM/AMBP-1 appears to be mediated through downregulation of proinflammatory cytokines.

Treatment With BX471, a Nonpeptide CCR1 Antagonist, Protects Mice Against Acute Pancreatitis-Associated Lung Injury by Modulating Neutrophil Recruitment

Chemokines and their receptors play a key role in the pathogenesis of acute pancreatitis. BX471 is a potent nonpeptide CC chemokine receptor 1 antagonist in both human and mouse. The aim of the present study was to evaluate the effect of prophylactic and therapeutic treatment with BX471 on experimental acute pancreatitis in the mouse and to investigate the underlying mechanisms. Acute pancreatitis was induced in mice by hourly intraperitoneal injection of cerulein. BX471 was administered either prophylactically or therapeutically, and pancreatic inflammation and lung injury were assessed. The expression of intercellular adhesion molecule 1, P-selectin, and E-selectin was studied by reverse transcriptase-polymerase chain reaction and immunohistochemistry. In cerulein-induced acute pancreatitis, treatment with BX471 significantly protected mice against lung injury associated with cerulein-induced pancreatitis by attenuating myeloperoxidase activity, an indicator of neutrophil recruitment, and lung morphological changes in histological sections. Treatment with BX471 had little effect on pancreatic damage. Blocking CC chemokine receptor 1 by BX471 also down-regulated intercellular adhesion molecule 1, P-selectin, and E-selectin expression at mRNA and protein levels in both lungs and pancreas compared with vehicle-treated groups. These findings suggest that interfering with neutrophil migration and activation by targeting CC chemokine receptor 1 may represent a promising strategy to prevent disease progression in acute pancreatitis.