Electrical impedance tomography is able to track changes in respiratory function in endotoxin-challenged rodents.

BACKGROUND AND OBJECTIVE: In order to assess and optimize the effect of new therapies for acute lung injury (ALI) in rodent models, a monitoring technique that continuously assesses the functional state of the lung is mandatory. Electrical impedance tomography (EIT) has been suggested as a technique for quantifying lung inflammation in ALI. However, EIT has not been evaluated in a rodent model of ALI. METHODS: EIT measurements were compared in ventilated Sprague-Dawley rats (n = 14), randomly subjected to intratracheal administration of endotoxin (LPS) or saline (control). Lung mechanics, lung weight wet/dry ratio and inflammatory markers in bronchoalveolar lavage fluid were also evaluated. RESULTS: LPS caused a significant decrease in lung compliance and TLC as compared with control (-42.0%, P = 0.04, and -27.9%, P = 0.02, respectively). These changes were paralleled by differences in mean impedance changes as detected by EIT (Spearman's rank correlation coefficient: rho = 0.66 and 0.73, respectively, P < 0.01). LPS increased the lung weight wet/dry ratio (6.35 +/- 0.42 vs 5.15 +/- 0.07, P = 0.003), and the bronchoalveolar lavage total WCC (8.96 +/- 1.87 vs 1.16 +/- 0.10 x 10(9)/L, P = 0.002) as compared with control. The lung weight wet/dry ratio was inversely related to the mean impedance change (rho = -0.76, P < 0.01). CONCLUSIONS: This study has demonstrated for the first time that eight-electrode EIT readily tracks the inflammatory response of lung tissue in a rodent model of ALI. EIT may thus provide a promising, non-invasive technique for monitoring the time-course of ALI in rodent models, and for testing novel pharmacological strategies to counter it.

Lung tissue mechanics predict lung hypoplasia in a rabbit model for congenital diaphragmatic hernia.

Several animal models have been proposed to study the pathophysiology of congenital diaphragmatic hernia (CDH). Surgical induction of CDH in fetal rabbits during the pseudoglandular phase has been shown to induce severe pulmonary hypoplasia, but functional studies in this model are scarce. We aimed to measure neonatal pulmonary impedance and related it to the severity of lung hypoplasia. CDH was surgically created in rabbits at 23 days of gestation. Following cesarean delivery at term (31 days) pups were subjected to measurement of total lung capacity (TLC), lung to body weight ratio (LBWR) and lung impedance by forced oscillation technique (FOT). Airway resistance (R(aw)), tissue elastance (H(L)), tissue damping (G(L)), and hysteresivity (eta) (G(L)/H(L)) were calculated from impedance data. Twelve CDH fetuses and 15 controls were available for final analysis. LBWR and TLC were significantly lower in the CDH group compared to gestational and age matched controls (P<0.001). R(aw), H(L), and G(L) were significantly increased in CCDH fetuses. eta and H(L) best reflected lung hypoplasia (LBWR) (r(2) = 0.42 and 0.43; P=0.001), indicating a dominant contribution of lung tissue mechanics to CDH-induced lung hypoplasia. We successfully introduced lung impedance measurement by FOT in neonatal rabbits. Following surgical induction of CDH in the pseudoglandular phase, they have, next to morphological evidence of pulmonary hypoplasia, changes in lung mechanics. Our results for lung tissue mechanics support the concept of delayed pulmonary tissue modeling. We propose to employ functional studies in future experiments when evaluating prenatal interventions aimed at reversing pulmonary hypoplasia.

CpG-free plasmid DNA prevents deterioration of pulmonary function in mice.

Nonviral gene vectors have been shown to be therapeutically effective in various animal models of inherited and acquired lung diseases. Although an acute unmethylated CG dinucleotide (CpG)-mediated inflammatory response has been previously observed for first-generation plasmids, its effect on pulmonary function has not been investigated to date. Here, we present data on lung functional parameters together with histopathology, cellular and inflammatory events in response to pulmonary administration of DNA-containing particles. We show that aerosol delivery of polyethylenimine gene vectors containing a first-generation CpG-rich plasmid induced an inflammatory response which was associated with a decrease in lung compliance. In contrast to these observations, aerosol application of CpG-free plasmid DNA prevented immune response and impairment of pulmonary function. These results demonstrate that aerosol delivery of CpG-free plasmid DNA is critical to avoid alteration of pulmonary function. Therefore, we suggest to use CpG-free pDNA for gene delivery to the lungs in future.

The effect of fetal tracheal occlusion on lung tissue mechanics and tissue composition.

Fetal tracheal occlusion (TO) is currently used to treat severe cases of congenital diaphragmatic hernia (DH). Clinical and experimental studies suggest an improved postnatal outcome, but lung tissue mechanics after TO have not been studied. We determined the effect of TO on mechanical impedance and lung tissue components in a rabbit model for DH. At 23 days of gestation (term = 31 days) either a sham thoracotomy or a diaphragmatic defect was induced. DH fetuses were randomly assigned to undergo 5 days later TO. Fetuses were delivered by term cesarean section to determine lung to body weight ratio (LBWR), dynamic lung mechanics and lung impedance. Airway resistance (R(aw)), elastance (H(L)), tissue damping (G(L)) and hysteresivity (G(L)/H(L)) were calculated from impedance data. Collagen I and III and elastin were quantified histologically. LBWR was significantly increased by TO compared to DH (P < 0.001) and resistance and compliance of the respiratory system (R(rs), C(rs)) were improved as well. TO resulted in a significant decrease of R(aw) comparable to observations in sham-fetuses, without effect on lung tissue mechanics H(L), G(L) and hysteresivity. This coincides with a significant decrease of collagen I, III and elastin in comparison to DH fetuses. In this first report on lung tissue mechanics in a rabbit model of DH, TO had a substantial effect on tissue morphology yet this was not mirrored in lung mechanics. We conclude that the effect of TO on lung mechanics without in utero reversal of occlusion, is dominated by airway remodeling.

Targeted delivery of magnetic aerosol droplets to the lung.

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory infection and, more recently, lung cancer. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles--so-called nanomagnetosols--in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.

Postnatal lung mechanics, lung composition, and surfactant synthesis after tracheal occlusion vs prenatal intrapulmonary instillation of perfluorocarbon in fetal rabbits.

BACKGROUND/PURPOSE: Fetal tracheal occlusion (TO) accelerates lung growth but decreases surfactant production. We have previously shown that instillation of perfluorooctylbromide (PFOB) into fetal rabbit lungs leads to lung growth similar to TO. This study compares neonatal lung mechanics and surfactant production after prenatal intrapulmonary PFOB instillation vs TO. METHODS: In each of 18 pregnant rabbits on gestational day 27, sets of 4 fetuses underwent either (1) intrapulmonary instillation of 1 mL PFOB, (2) TO, (3) instillation of 1 mL 0.9% NaCl (saline), and (4) hysteroamniotomy without fetal manipulation (control). Fetuses were born by cesarean delivery after 48 hours. Fetuses of 12 rabbits were mechanically ventilated for 15 minutes to evaluate lung compliance and airway resistance. Pulmonary surfactant protein B (SP-B) was quantified by immunohistochemistry in fetuses of the remaining 6 rabbits. RESULTS: Compliance was decreased in the TO group after cesarean delivery (0.33 +/- 0.13 mL/cm H2O) compared with PFOB (0.59 +/- 0.12 mL/cm H2O), saline (0.50 +/- 0.12 mL/cm H2O), and control (0.52 +/- 0.10 mL/cm H2O) fetuses. Mean fetal lung to body weight ratio was higher in TO and PFOB fetuses compared with saline and control. Higher water content and lower numbers of surfactant protein B-positive cells were found in the TO-treated fetuses. CONCLUSIONS: Both prenatal intrapulmonary instillation of PFOB and TO accelerate lung growth, but TO is associated with decreased postnatal lung compliance, possibly influenced by decreased surfactant production and increased fluid retention. Conversely, instillation of PFOB preserved lung compliance and surfactant synthesis.