Gram Of Lung Tissue Research Articles

A Rapid Human Lung Tissue Dissociation Protocol Maximizing Cell Yield and Minimizing Cellular Stress.

The human lung is a complex organ comprised of diverse populations of epithelial, mesenchymal, vascular and immune cells, which gains even greater complexity during disease states. To effectively study the lung at a single cell level, a dissociation protocol that achieves the highest yield of viable cells of interest with minimal dissociation-associated protein or transcription changes key. Here, we detail a rapid collagenase-based dissociation protocol (Col-Short), which provides a high-yield single cell suspension suitable for a variety of downstream applications. Diseased human lung explants were obtained and dissociated through the Col-Short protocol and compared to four other dissociation protocols. Resulting single cell suspensions were then assessed with flow cytometry, differential staining, and quantitative real-time PCR to identify major hematopoietic and non-hematopoietic cell populations, as well as their activation states. We observed that the Col-Short protocol provides the greatest number of cells per gram of lung tissue with no reduction in viability when compared to previously described dissociation protocols. Col-Short had no observable surface protein marker cleavage as well as lower expression of protein activation markers and stress-related transcripts compared to four other protocols. The Col-Short dissociation protocol can be used as a rapid strategy to generate single cells for respiratory cell biology research.

Non-invasive endotracheal delivery of paclitaxel-loaded alginate microparticles

Aerosolized chemotherapeutics leads to higher, localized and continuous concentrations of active agents in lung tissue with lower side effects for other organs. The present study was performed on jugular vein cannulated rats which endothracheally received 4 mg/kg of free paclitaxel powder (Free-PTX), paclitaxel-loaded alginate microparticles (PTX-ALG-MPs) and i.v. paclitaxel (Anzatax®). Pharmacokinetic parameters for Free-PTX and PTX-ALG-MPs contain higher AUC, mean residence time (MRT),half-life and bioavailability, with lower elimination constant (ke). Statistical analysis showed that the amount of paclitaxel per gram of lung tissue after 0.5, 6 and 24 h after administration of Free-PTX was lower than PTX-ALG-MPs. Lung tissue AUC for Free-PTX was lower than PTX-ALG-MPs. According to the obvious advantages obtained, such as dose lowering and increasing paclitaxel residence time and half-life. It should be noted that cell cytotoxicity test on normal airway cell lines was not examined in this study but due to previous reports on safety of inhaled paclitaxel, it can be suggested that pulmonary delivery of paclitaxel can be a useful non-invasive route of administration compared with i.v administration.

PROTECTIVE EFFECTS OF HYDROALCOHOLIC EXTRACT OF HYPERICUM PERFORATUM AGAINST BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN RATS

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis is a chronic interstitial lung disease caused by parenchymal lung damage due to inflammatory factors and fibrosis. Hypericum perforatum contains various flavonoids with antioxidant properties. This study aimed to evaluate protective effects of hydroalcoholic extract of Hypericum against bleomycin-induced pulmonary fibrosis in rats. METHODS: This empirical study was conducted on 30 Wistar rats weighing 150-180 grams. Animals were randomly divided into five groups of six. Group one received a single dose of normal saline intraperitoneally, and group two was administered with bleomycin (7.5 units per kg) intratracheally. Other groups received daily doses of Hypericum extract (50, 100 and 200 mg/kg) via intraperitoneal injection one week before and two weeks after bleomycin administration. After 21 days, animals were sacrificed, and blood and lungs were collected for histopathological examinations, and measurement of plasma malondialdehyde (MDA) and lung hydroxyproline (HP). FINDINGS: In this study, lung index, HP and plasma MDA in normal saline group were respectively 7.09±0.32 mg per kilogram of body weight, 1.80±0.23 mg per gram of lung tissue, and 1.32±0.27 micromoles per liter of plasma. In rats administered with bleomycin, these values were 9.75±0.90, 5.43±0.7 and 3.04±0.42, respectively. Treatment with Hypericum extract, especially at dosage of 200 mg/kg, resulted in a significant reduction in the aforementioned parameters compared to bleomycin group (p<0.05). CONCLUSION: According to the results of this study, hydroalcoholic extract of Hypericum perforatum could exert protective effects against bleomycin-induced pulmonary fibrosis.

Novel multi-functional europium-doped gadolinium oxide nanoparticle aerosols facilitate the study of deposition in the developing rat lung.

Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg m(-3) of ∼30 nm europium doped gadolinium oxide nanoparticles (Gd2O3:Eu(3+)) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng per g body weight compared to 1.47 ng per g and 0.097 ng per g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution.

Identification of ferruginous bodies in the lungs of children and analyses of the elemental composition of fibers

Ferruginous bodies (FBs) are iron-coated entities that form in the body around inorganic fibers or other particulates that can serve as indicators of exposure to inorganic dust. Studies of FB have been conducted consistently in the lungs of adults but have not been explored in children during the past 20 years. The objective of this work was to quantify the FB, classify them as to morphological type and conduct a mineralogical analysis using the energy dispersive X-ray microanalysis (EDXA) with samples obtained from 72 autopsies performed on children. Three grams of lung tissue were digested in commercial bleach, and all the FB found were quantified. The FB from the positive cases was analyzed by EDXA. Results show that 17% of cases presented FB with a median concentration of 5.7 ferruginous bodies per gram of dry weight (FB/g). Larger quantities of FB were recovered from the lungs of rural residents, at concentrations of 11.33 FB/g. Ten cases of children under 5 years of age also presented 5.7 FB/g, but none of these groups showed significant differences when compared to populations of children residing in Mexico City or to children over 5 years of age (p > 0.05). Type-1 FB was the predominant morphological form present. All FB were aluminosilicates. It can be concluded that Mexican children retain FB at low concentrations. All the cores of the FB analyzed in this study were aluminosilicates. Only one contained kaolinite, while the other 10 consisted of some kind of feldspar or clay-like mineral and may thus reflect intramural exposure in children.

Bronchoscopic thermal vapor ablation in a canine model of emphysema

Clinical studies indicate the potential of bronchoscopic thermal vapor ablation to result in clinically relevant improvements in severe chronic obstructive pulmonary disease patients with upper lobe-predominant emphysema. However, the mechanisms by which vapor ablation results in lung volume reduction are not fully known. This study determined the 3-month safety and efficacy of vapor ablation in a canine model of emphysema and described the histopathological changes in the lung. The cranial lobes of papain-exposed dogs were treated with a vapor dose of ten calories per gram of lung tissue (n = 8) or were sham treated (n = 3). Safety was monitored peri- and postoperatively for 3 months. Animals were then sacrificed, estimates of lung volume reduction performed, and the lungs processed for histology. Vapor ablation was associated with an average of 20% volume reduction of the treated lobes and an absence of serious adverse events. The amount of lobar volume reduction was correlated with the amount of fibrosis and atelectasis in the treated lobe. Bronchoscopic thermal vapor ablation at a dose of 10 cal/g results in lobar volume reduction associated with remodeling of the targeted tissue characterized by mature collagen formation in the absence of major adverse events.

Clinical study of asbestos‐related lung cancer in Japan with special reference to occupational history

A total of 152 patients with asbestos-related lung cancer recognized by the criteria of Japanese compensation law for asbestos-related diseases were examined and compared with 431 patients with non-asbestos-related lung cancer. Male comprised 96% of patients. Ages ranged from 50 to 91 years with a median of 72 years. Eighty-nine percent were smokers or ex-smokers. Almost all patients had occupational histories of asbestos exposure. The median duration of asbestos exposure was 31 years and the median latency period was 47 years. Thirty-four percent of patients exhibited asbestosis and 81% exhibited pleural plaques by radiography. Regarding asbestos particles in the lung for 73 operated or autopsied patients, 62% had more than 5,000 particles per gram. On the other hand, 100% of non-asbestos-related lung cancer patients had <5000 particles per gram with a median of 554 particles. The number of asbestos bodies in the lung, male gender, absence of symptoms, smoking index, and early stage of cancer were significantly much more than those of non-asbestos-related lung cancer. In this study, a diagnosis of asbestos-related lung cancer was made in 34% of patients by asbestosis, in 62% by presence of both pleural plaques and more than 10 years' occupational asbestos exposure, and in 4% by more than 5000 asbestos particles per gram of lung tissue. Occupational histories, duration of asbestos exposure, and pleural plaques are common categories for the recognition of asbestos-related lung cancer in Japan.

Pulmonary Deposition of Aerosolized Bacillus Atrophaeus in a Swine Model Due to Exposure from a Simulated Anthrax Letter Incident

Dry anthrax spore powder is readily disseminated as an aerosol and it is possible that passive dispersion when opening a letter containing anthrax spores may result in lethal doses to humans. The specific aim of this study was to quantify the respirable aerosol hazard associated with opening an envelope/letter contaminated with a dry spore powder of the biological pathogen anthrax in a typical office environment. An envelope containing a letter contaminated with 1.0 g of dry Bacillus atrophaeus (BG) spores (pathogen simulant) was opened in the presence of an unrestrained swine model. Aerosolized spores were detected in the room in seconds and peak concentrations occurred by three minutes. The swine, located approximately 1.5 m from the source, was exposed to the aerosol for 28 min following the letter opening event and then moved to a clean room for 30 min. A necropsy was completed to determine the extent of in vivo spore deposition in the lungs. The median number of viable colony forming units (CFU) measured in the combined right and left lung was 21,200: the average mass of both lungs was 283 g. In excess of 100 CFU per gram of lung tissue was found at sites within the anterior, intermediate and posterior lobes. The results of this study confirmed that opening an envelope containing spores generated an aerosol spanning the respirable particle size range of 1–10 μm, and that normal respiration of swine led to spore deposition throughout the lungs. The observed deposition of spores in the lungs of the swine is within the LD50 range of 2,500–55,000 estimated for humans for inhaled anthrax. Thus, there would appear to be a significant health risk to those individuals exposed to anthrax spores when opening a contaminated envelope.

Lung Aeration During Sleep

Background:During sleep, ventilation and functional residual capacity (FRC) decrease slightly. This study addresses regional lung aeration during wakefulness and sleep.Methods:Ten healthy subjects underwent spirometry awake and with polysomnography, including pulse oximetry, and also CT when awake and during sleep. Lung aeration in different lung regions was analyzed. Another three subjects were studied awake to develop a protocol for dynamic CT scanning during breathing.Results:Aeration in the dorsal, dependent lung region decreased from a mean of 1.14 ± 0.34 mL (± SD) of gas per gram of lung tissue during wakefulness to 1.04 ± 0.29 mL/g during non-rapid eye movement (NREM) sleep (− 9%) [p = 0.034]. In contrast, aeration increased in the most ventral, nondependent lung region, from 3.52 ± 0.77 to 3.73 ± 0.83 mL/g (+ 6%) [p = 0.007]. In one subject studied during rapid eye movement (REM) sleep, aeration decreased from 0.84 to 0.65 mL/g (− 23%). The fall in dorsal lung aeration during sleep correlated to awake FRC (R2= 0.60; p = 0.008). Airway closure, measured awake, occurred near and sometimes above the FRC level. Ventilation tended to be larger in dependent, dorsal lung regions, both awake and during sleep (upper region vs lower region, 3.8% vs 4.9% awake, p = 0.16, and 4.5% vs 5.5% asleep, p = 0.09, respectively).Conclusions:Aeration is reduced in dependent lung regions and increased in ventral regions during NREM and REM sleep. Ventilation was more uniformly distributed between upper and lower lung regions than has previously been reported in awake, upright subjects. Reduced respiratory muscle tone and airway closure are likely causative factors.

Ceftobiprole medocaril (BAL5788) treatment of experimental Haemophilus influenzae, Enterobacter cloacae, and Klebsiella pneumoniae murine pneumonia

Ceftobiprole (BAL9141) is an investigational cephalosporin active against methicillin- and vancomycin-resistant staphylococci administered as a water-soluble prodrug, ceftobiprole medocaril (BAL5788). Using an immunocompetent murine pneumonia model of Haemophilus influenzae, Enterobacter cloacae, or extended-spectrum β-lactamase (ESBL) nonproducing or producing Klebsiella pneumoniae pneumonia, we compared results of treatment with ceftobiprole medocaril (71 mg/kg, sc, qid), ceftriaxone (50 mg/kg, im, bid), or cefepime (50 mg/kg, ip, q.i.d.). Results were expressed as median and 25th to 75th percentile log 10 colony forming units per gram of lung tissue. Ceftobiprole, ceftriaxone, and cefepime were each more active than was no treatment and were equally active for treatment of experimental H. influenzae, E. cloacae, or ESBL-nonproducing K. pneumoniae pneumonia. For ESBL-producing K. pneumoniae, no differences were detected between no treatment and treatment with ceftobiprole, ceftriaxone, or cefepime. Ceftobiprole is active against H. influenzae, E. cloacae, and ESBL-nonproducing K. pneumoniae in an immunocompetent experimental murine pneumonia model.

Responses to ozone are increased in obese mice.

Epidemiological data indicate an increased incidence of asthma in overweight adults and children. Ozone (O3) is a common trigger for asthma. Accordingly, the purpose of this study was to compare O3-induced airway hyperresponsiveness and airway inflammation in lean, wild-type (C57BL/6J) mice and mice that are obese as a consequence of a genetic defect in the gene encoding the satiety hormone leptin (ob/ob mice). The ob/ob mice eat excessively and weighed more than twice as much as age- and gender-matched wild-type mice. Airway responsiveness to intravenous methacholine was measured by forced oscillation. In air-exposed controls, baseline pulmonary resistance was greater, and the dose of methacholine required to double pulmonary resistance was lower in ob/ob than wild-type mice. Exposure to O3 (2 parts/million for 3 h) caused AHR and airway inflammation in both groups of mice, but responses to O3 were enhanced in ob/ob compared with wild-type mice. Administration of exogenous leptin did not reverse the enhanced inflammatory response observed in ob/ob mice, but augmented airway inflammation in wild-type mice. The inhaled dose of O3 per gram of lung tissue was greater in ob/ob than wild-type mice. Our results indicate that O3-induced airway responses are enhanced in ob/ob mice and suggest that inhaled O3 dose may be one factor contributing to this difference, but other aspects of the obese phenotype may also contribute. Our results also indicate that the hormone leptin, which is increased in the obese, has the capacity to increase airway inflammation.

Minimization of Pathologic Changes in Ornithobacterium rhinotracheale Infection in Turkeys by Temperature-Sensitive Mutant Strain

The protection elicited by a temperature-sensitive (Ts) mutant of Ornithobacterium rhinotracheale (ORT) vaccine against challenge with pathogenic strain was investigated. In Experiment 1, specific serologic response to ORT was detected in 12%-19% of Ts-vaccinated birds at 3 wk postvaccination by either drinking water or oculo-nasal instillation. At 7 days postchallenge, 100% of Ts-vaccinated turkeys of all groups were able to respond with an ORT-specific antibody response, but the control group was not, suggesting the potential of Ts strain to evoke immune protection. The study also revealed a statistically significant ability of the Ts strain to protect vaccinated turkeys against gross lesions caused by the pathogenic strain of ORT in treated groups vs. control. In Experiment 2, seroconversion was detected by enzyme-linked immunosorbent assay in birds after they were given the Ts strain in drinking water in field conditions. The results of the field study showed mean scores of gross lesions of nonvaccinated/challenged groups to be up to seven times higher than those of the vaccinated/challenged group. In addition, reisolation rates and quantification of ORT colonies per gram of lung tissue were significantly lower for vaccinated/challenged than for nonvaccinated/challenged turkeys. In conclusion, results from laboratory and field experiments suggest that use of the Ts mutant strain of ORT as a live vaccine would be a suitable method to evoke protection against ORT infection in turkeys.

Effect of surfactant and specific antibody on bacterial proliferation and lung function in experimental pneumococcal pneumonia

Objective: To investigate the effect of surfactant and specific antibody on bacterial proliferation in experimental pneumococcal pneumonia. Methods: Near-term newborn rabbits received a standard dose (107) of type 3 pneumococci via the airways. Control animals were sacrificed 1 minute later. Other animals were ventilated for 5 hours and treated via the tracheal cannula with surfactant (Curosurf 200 mg/kg), a mixture of surfactant and a polyclonal antipneumococcal antibody, the antibody without surfactant, or saline. Results: There was a significant bacterial proliferation in lung tissue in all animals ventilated for 5 hours. Bacterial growth, expressed as log 10 colony forming units (CFU) per gram of lung tissue was less prominent in animals treated with a mixture of surfactant and specific antibody than in animals treated with antibody alone (median, 7.51, range, 6–7 vs. median, 7.92, range, 7.07–8.50; P < 0.05). Dynamic lung-thorax compliance was improved with surfactant or surfactant plus antibody in comparison with saline or antibody alone. Conclusion: The data suggest that the suppressive effect of the antibody on bacterial proliferation becomes evident only when surfactant is administered together with the antibody.

Lung cancer and past occupational exposure to asbestos. Role of p53 and K-ras mutations.

Studies on somatic mutations in lung cancers associated with cigarette smoking and asbestos exposure are few. We investigated prevalence of mutations in the p53 and K-ras genes in lung tumors from smokers with and without asbestos exposure at work. For K-ras mutations, the study was an extension of an earlier analysis. Nearly all of the 105 consecutive patients examined were smokers and had non-small-cell carcinoma of the lung with squamous-cell carcinoma or adenocarcinoma histology. Exposure to asbestos was estimated by pulmonary fiber counts and occupational histories. A pulmonary burden of >/= 1 x 10(6) asbestos fibers per gram of lung tissue, indicating work-related exposure, was found in 32% of the patients for whom fiber-analysis data were available (33 of 102 patients, all men). The statistical analysis showed pulmonary fiber count as the only significant predictor of adenocarcinoma histology, in contrast to squamous-cell carcinoma (smoking-adjusted odds ratio [OR] 3.0, 95% confidence interval [CI] 1.1 to 8.5). The frequency of p53 mutations was 39% (13 of 33) among the asbestos-exposed cases, as compared with 54% (29 of 54) among the nonexposed cases; the difference was not significant, however. In male ever-smokers, a long duration of smoking was associated with p53 mutation (OR 3.2, 95% CI 1.2 to 8.8). In adenocarcinoma, p53 mutations were less prevalent (10 of 30, 33%) as compared with squamous-cell carcinoma (28 of 46, 61%; P = 0.02), whereas a strong and significant association was found between adenocarcinoma and K-ras mutation (OR 37, 95% CI 5.8 to 232, adjusted for smoking and asbestos exposure). Asbestos exposure alone was not significantly associated with increased occurrence of K-ras mutations. In conclusion, the results may primarily reflect the observed excess of adenocarcinoma in the asbestos- exposed patients, and hence the decrease in p53 mutations and increase in K-ras mutations.

Preclinical models for Chlamydia pneumoniae and cardiovascular disease: hypercholesterolemic mice

Seroepidemiologic studies have shown an association of Chlamydia pneumoniae antibody with atherosclerosis. Compelling additional evidence has accumulated, in that the organism has been found within atherosclerotic lesions throughout the arterial tree by multiple methods. C. pneumoniae has also been isolated from coronary and carotid atheromatous plaques. Although these studies support a potential role for C. pneumoniae in atherogenesis, confirmation of a causal relationship requires the use of animal models and intervention studies. We have focused on the evaluation of mouse models to address the hypothesis that, following upper respiratory tract infection, lung macrophages are infected, disseminate to the aorta, and alter the onset or progression of atherogenesis. ApoE-deficient knock-out and C57BL/6J mice were used. The apoE-deficient mouse develops atherosclerotic lesions spontaneously on a regular diet in a time- and age-dependent manner. This knock-out strain was developed on the background of the C57BL/6J mouse, which only develops atherosclerosis on a high-fat/high-cholesterol diet. To investigate whether infected macrophages constitute a vehicle for dissemination of C. pneumoniae in vivo, mice were inoculated intranasally or intraperitoneally. The organism was detected in harvested alveolar and peritoneal macrophages at all time points following intranasal and intraperitoneal inoculations, respectively, and in peripheral blood mononuclear cells following inoculation by both routes. In another experiment, alveolar and peritoneal macrophages from intranasally and intraperitoneally inoculated mice were adoptively transferred by intraperitoneal injection to uninfected mice. Subsequently, C. pneumoniae was detected in lung, spleen, abdominal lymph nodes and/or thymus of recipient mice. In control experiments, UV-inactivated C. pneumoniae DNA was not detected in alveolar or peritoneal macrophages beyond 5 min after inoculation in vivo. These cumulative results demonstrate that C. pneumoniae infects macrophages in vivo and that macrophages can serve as a vehicle for dissemination to other sites. To answer the question of whether the organism disseminates to and persists in the aorta, 8-week-old mice were infected intranasally. Following single or multiple inoculations in apoE-deficient mice, C. pneumoniae was detected in the lung and aorta for 20 weeks postinfection. In contrast, in C57BL/6J mice, the organism did not persist in the aorta following a single intranasal inoculation, but could be detected up to 7 weeks postinfection in multiply inoculated mice. Significantly, in apoE-deficient mice with developed atherosclerotic lesions, the organism was found in foam cells within the lesions by immunocytochemical staining. These studies show that persistent C. pneumoniae infection occurs in atherosclerotic lesions in the aorta in the apoE-deficient knock-out mouse model. Infection of the aorta also occurred in C57BL/6J mice but was more transient. Both models should be useful in studying the pathogenic role of C. pneumoniae in atherogenesis and for determining if therapy prevents dissemination of infection. To this end, we have evaluated the susceptibility of C. pneumoniae to roxithromycin, a new macrolide, in vitro in cell culture and in vivo in the apoE-deficient mouse model. In vitro results compare favorably with other new macrolides, quinolines, and tetracyline. Preliminary studies in the apoE model of persistent infection suggest that the organism is detected less frequently in the lung and aorta by PCR following treatment. These promising preliminary studies warrant further investigation.

Minimum protective serum concentrations of pneumococcal anti-capsular antibodies in infant rats.

Infant rats were passively immunized to determine the protective capacity of pneumococcal anticapsular antibodies. Animal-passaged strains of Streptococcus pneumoniae serotypes 1, 4, 5, 6b, 7f, 9v, 14, 18c, 19f, and 23f were used as challenge inocula (1-1500 cfu) in a model of pulmonary infection that resulted in bacteremia, meningitis, and death. From untreated control animals, histologic sections of lung demonstrated infiltrative pneumonia and lung homogenate cultures grew S. pneumoniae at concentrations of 10(3)-10(8) cfu per gram of lung tissue. A type-specific anti-capsular antibody serum concentration of 0.1-1.15 microg/mL resulted in a statistically significant reduction in mortality compared with the reduction in untreated controls, except for serotype 14, which required 2.32 microg/mL for a significant reduction in mortality. The serum antibody level that provided 50% reduction in mortality ranged from 0.1-3.5 microg/mL for all serotypes.

Malignant mesothelioma following treatment for Hodgkin's disease.

Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma. Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature. In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship. Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma.

Pathophysiology of congenital diaphragmatic hernia XVI: Elevated pulmonary collagen in the lamb model of congenital diaphragmatic hernia

The pathophysiologic features of congenital diaphragmatic hernia (CDH) include pulmonary hypoplasia, pulmonary hypertension, surfactant deficiency, and decreased pulmonary compliance. When the surfactant deficiency is corrected using exogenous surfactant therapy, the pulmonary compliance improves, but does not reach normal values. Quasistatic saline pressure-volume measurements, which eliminate the air-liquid interface, confirm that CDH lungs are intrinsically less compliant than control lungs. The authors hypothesized that this abnormal lung compliance results from elevated concentrations of collagen and/or elastin in the lung. Therefore, they measured the collagen and elastin concentrations in CDH and control lung tissue. Also measured was the collagen concentration in the kidney, intestine, and dissected third-generation arterioles, venules, and bronchioles, to characterize further the pathology of CDH. The CDH model was created on the left side of fetuses in pregnant ewes at 80 days' gestation. The fetuses were delivered and killed at 140 days (full term, 145). The concentrations of collagen (as hydroxyroline), elastin, DNA, and total protein were measured using standard techniques. Although there was significantly more collagen per gram of lung tissue in the CDH lungs (1.334 mg/g v 0.885 mg/g in the controls) the elastin concentrations were not different. The elevated collagen concentration was not associated specifically with the conducting airways or vasculature. The collagen concentrations in CDH kidneys and intestines were the same as those of controls. The DNA/total protein ratios in the CDH and control lungs were identical. The results suggest that the elevated collagen concentration was present only in the lungs of CDH lambs, and that it was not attributable to atrophy or hypertrophy of the lungs. Thus, increased collagen in the lung parenchyma may be responsible for the intrinsic stiffness and decreased compliance of the CDH lungs.

Postnatal growth of lung parenchyma in the piglet: Morphometry correlated with mechanics

A previous study of piglet lung growth (Mansell et. al. 1989. J. Appl. Physiol., 67:1422-1427) showed transient stiffness to changes in shape and volume immediately after birth. Later, elastic recoil was found to increase as the lung grew in weight and volume. The present study uses morphometry to test possible structural correlates of these two mechanical changes. Piglet lungs were fixed near full inflation via the airways during the immediate newborn period (6-12 hours, n = 3), at 3-5 days (n = 6), 25-30 days (n = 5), and 80-85 days (n = 3). Morphometry comprised arithmetic and harmonic mean thicknesses of alveolar septae and average mean surface curvature. Measurements of curvature and airspace volume were combined to differentiate alveolar expansion from septal proliferation as mechanisms for volumetric growth. The unique mechanical behavior of the newborn lungs was associated with relatively thick alveolar septae. Marked thinning of the septae and resolution of the stiffness to shape and volume change had occurred by 3-5 days. An increase in elastic recoil during the first postnatal month was found to be associated with simple airspace expansion. The second and third months were characterized by septal proliferation and increase in arithmetic mean septal thickness but elastic recoil did not increase further. Harmonic mean septal thickness and airspace volume per gram of lung tissue did not change over the course of the study. 1) A relative stiffness to shape and volume change in freshly newborn piglet lungs is associated with relatively thick alveolar septal walls; 2) postnatal development of piglet lung parenchyma involves septal lengthening and thinning followed by septal proliferation; 3) the initial phase of septal lengthening, rather than the later phase of septal proliferation, is associated with increase in parenchymal recoil.

Pathophysiology of congenital diaphragmatic hernia IX: Correlation of surfactant maturation with fetal cortisol and triiodothyronine concentration

In addition to pulmonary hypoplasia and an altered pulmonary vascular bed, the abnormal lung development caused by congenital diaphragmatic hernia (CDH) is associated with an impairment in the pulmonary surfactant system. The aim of this study was to correlate fetal serum cortisol and triiodothyronine (T 3) levels, known indicators of surfactant development, with maturation of the surfactant system in the lamb CDH model. Analysis of the products of bronchoalveolar lavage in CDH showed decreased phospholipid ( P < .01) and increased protein concentration ( P < .02) per gram of lung tissue when compared with controls, but cortisol and T 3 concentrations did not differ significantly between the two groups. These results suggest that the surfactant deficiency in CDH is not related to an alteration in cortisol or T 3 levels but may be directly related to the mechanical effects of the intrathoracic bowel.