Changes In Lung Disease Research Articles

The Oral Microbiome and Lung Diseases

The understanding of the human microbiome, especially of the oral cavity, has expanded exponentially since the advent of 16 rRNA PCR gene sequencing. Since the respiratory tract starts from the oral cavity and ends in the lung, study of the relationship between the oral microbiota and the lungs will allow us to understand the changes in lung disease compared with healthy state. The oral and lung microbiota were found to be similar, but the oral microbiota had greater diversity. The oral cavity especially the dorsal tongue was found to be a reservoir for bacteria causing pneumonia and chronic lung infection in cystic fibrosis. Oral and lung infections seem to all share the similar pathogenesis of oral microbiota dysbiosis. Certain oral bacteria were found to be potential biomarkers for lung cancer. Improvement in oral health is important especially in the management of lung diseases with infectious etiology. Oral microbiota can serve as biomarkers for diseases especially in lung cancer.

Peptide PD29 treats bleomycin-induced pulmonary fibrosis by inhibiting the TGF-β/smad signaling pathway

Pulmonary fibrosis (PF) is an end-stage change in lung disease characterized by fibroblast proliferation, massive extracellular matrix (ECM) aggregation with inflammatory damage, and severe structural deterioration. PD29 is a 29-amino acid peptide which has the potential to alleviate PF pathogenesis via three mechanisms: anti-angiogenesis, inhibition of matrix metalloproteinase activities, and inhibition of integrins. In this study, fibrotic lung injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administered 7.5, 5, or 2.5 mg/kg PD29 daily for 30 days. BLM induced-syndromes including structure distortion, excessive deposition of ECM, excessive inflammatory infiltration, and pro-inflammatory cytokine release were used to evaluate the protective effect of PD-29. Oxidative stress damage in lung tissues was attenuated by PD29 in a dose-dependent manner. The expression of TGF-β1 and the phosphorylation of Smad-2/-3—its downstream targets—were enhanced by BLM and weakened by PD29. In vitro, PD29 inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and transformation in A549 cells and mouse primary fibroblasts into myofibroblasts. In summary, PD29 reversed EMT and transformation of fibroblasts into myofibroblasts in vitro and prevented PF in vivo possibly by suppressing the TGF-β1/Smad pathway.

A simulation study of diffusion-convection interaction and its effect on multiple breath washout indices

Experimental studies of acinar ventilation heterogeneity (Sacin) derived from the multiple breath washout have shown the potential of Sacin to pick up structural change in lung disease. Recent Sacin data suggest that even when intra-acinar structure is unaltered, the combination of convection, diffusion and number of acini fed by patent terminal bronchioles can modify Sacin. We show here how Sacin is affected by structural features such as the secondary alveolar septa, intra-acinar ramification and number of ventilated acini. The simulations also predict relationships between respective alterations in Sacin and washout indices such as lung clearance index (LCI) and alveolar mixing efficiency (AME). This was verified experimentally, with highly significant correlations between Sacin and LCI (r = +0.85;p < 0.001) and between Sacin and AME (r = − 0.92; p < 0.001). We have shown how acinar ventilation heterogeneity can be affected by a reduction of number of ventilated acini, a change in overall alveolization or in intra-acinar alveolization pattern, via their impact on the balance between convection and diffusion at acinar level.

Changes in Pulmonary Function and Controlled Ventilation-High Resolution CT of Chest After Antibiotic Therapy in Infants and Young Children with Cystic Fibrosis.

Infants with cystic fibrosis (CF) develop early progressive lung disease which may be asymptomatic. Infant pulmonary function tests (IPFT) and controlled ventilation-high resolution computed tomography (CV-HRCT) of chest can detect early asymptomatic lung disease. It is not well established that these objective measures can detect changes in lung disease after clinical interventions. The purpose of this study was to evaluate usefulness of IPFT and CV-HRCT to detect changes in lung disease after intravenous (IV) antibiotic therapy in infants with early CF-related lung disease. IPFTs and CV-HRCT done before and after 2 weeks of IV antibiotics in infants at our institution over the last 12 years were compared. CV-HRCTs were compared using the modified Brody scoring system. The sample included 21 infants, mean age 85.2 ± 47.6 weeks. Mean change in weight was 0.4 ± 0.38 kg (p = 0.001). Significant changes in IPFT included mean % predicted FEV(0.5) (+13.5 %, p = 0.043), mean %FEF(25-75) (+30.2 %, p = 0.008), mean %RV/TLC (-11.2 %, p = 0.008), and mean %FRC/TLC (-4.5 %, p = 0.001). Total Brody scores improved from a median of 10 to 5 (p < 0.001) as did mean scores for airway wall thickening (p = 0.050), air trapping (p < 0.001), and parenchymal opacities (p = 0.003). IPFT and CV-HRCT can be used as objective measures of improvement in lung disease for infants with CF treated with antibiotics.

Quantitative Computerized Two-Point Correlation Analysis of Lung CT Scans Correlates With Pulmonary Function in Pulmonary Sarcoidosis

Chest CT scans are commonly used to clinically assess disease severity in patients presenting with pulmonary sarcoidosis. Despite their ability to reliably detect subtle changes in lung disease, the utility of chest CT scans for guiding therapy is limited by the fact that image interpretation by radiologists is qualitative and highly variable. We sought to create a computerized CT image analysis tool that would provide quantitative and clinically relevant information. We established that a two-point correlation analysis approach reduced the background signal attendant to normal lung structures, such as blood vessels, airways, and lymphatics while highlighting diseased tissue. This approach was applied to multiple lung fields to generate an overall lung texture score (LTS) representing the quantity of diseased lung parenchyma. Using deidentified lung CT scan and pulmonary function test (PFT) data from The Ohio State University Medical Center's Information Warehouse, we analyzed 71 consecutive CT scans from patients with sarcoidosis for whom simultaneous matching PFTs were available to determine whether the LTS correlated with standard PFT results. We found a high correlation between LTS and FVC, total lung capacity, and diffusing capacity of the lung for carbon monoxide (P &lt; .0001 for all comparisons). Moreover, LTS was equivalent to PFTs for the detection of active lung disease. The image analysis protocol was conducted quickly (&lt; 1 min per study) on a standard laptop computer connected to a publicly available National Institutes of Health ImageJ toolkit. The two-point image analysis tool is highly practical and appears to reliably assess lung disease severity. We predict that this tool will be useful for clinical and research applications.

Chest computed tomography scores of severity are associated with future lung disease progression in children with cystic fibrosis.

Most children with cystic fibrosis (CF) experience a slow decline in spirometry, although some children continue to be at risk for more significant lung disease progression. Chest computed tomography (CT) scans have been shown to be more sensitive to changes in lung disease than spirometry and may provide a means for predicting future lung disease progression. We hypothesized that Brody chest CT scan scores obtained in 2000 in a prospectively monitored cohort of children with CF would be associated with the most recent measures of lung disease severity. Brody chest CT scan scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. Multivariable linear regression was used to determine associations between Brody scores and the most recent (age 21 yr or June 30, 2010, whichever was later) measures of CF lung disease. The mean observation time after the chest CT scan was 7.5 years. Brody chest CT scan scores were significantly associated with the most recent measures of spirometry (P < 0.001) and Wisconsin and Brasfield chest radiograph scores (P < 0.001). The strength of this association was much stronger than spirometry obtained near the time of the chest CT scan (P < 0.01) but not chest radiograph scores. Chest CT scan scores are associated with future lung disease severity, and quantitative chest imaging(chest CT scan and chest radiograph scores) is more strongly associated with future lung disease severity than measures of spirometry. These findings may help clinicians identify patients at risk of future lung disease progression.

It's Not All Smooth Muscle: Non-Smooth-Muscle Elements in Control of Resistance to Airflow

To achieve gas exchange, inspired air must pass through an intricate and dynamic tracheobronchial tree. The tree offers resistance to airflow, and increased resistance is the most important functional change in lung disease. Numerous mechanisms contribute to increased resistance by causing airway narrowing, closure, occlusion, and/or obliteration. Although airway smooth muscle (ASM) contraction and shortening are an important cause of increased resistance, non-ASM elements can also contribute. Nonmuscle elements can modify the amount of airway narrowing for any given level of ASM shortening and the amount of shortening for a given level of ASM activation. In this review, we outline the physiological basis for airflow resistance and describe how changes in the lung parenchyma, the airways, and their luminal contents can contribute to increased airflow resistance. A detailed understanding of the mechanisms and consequences of increased airway resistance is vital to our attempts to alleviate the enormous burden of suffering caused by obstructive lung diseases.

Use of Lung Imaging Studies as Outcome Measures for Development of New Therapies in Cystic Fibrosis

Most cystic fibrosis (CF) drug development has been based upon functional outcomes (e.g., FEV(1)) rather than structural changes. This functional approach has the limitation of being insensitive of early changes in lung disease. Computer tomography (CT) scanning affords the opportunity to establish a new paradigm to stage the illness (and target populations) based upon morphology. Using this concept, treatment regimens would be tested to prevent progression, reverse early changes, or stabilize established structural damage. In this setting, imaging biomarkers could play a key role. This article reviews the potential uses of CT scanning in the different phases of drug development (phase 1 to 4 studies). In early-phase studies (i.e., human pharmacology and therapeutic exploratory trials), CT could be used to provide preliminary data on mechanisms of action and efficacy. For large phase 3, therapeutic, confirmatory trials, CT scans are less likely to be the primary endpoint, but may play a supportive role in clinical efficacy measures and subset analyses (e.g., infants). For postmarketing therapeutic use trials, CT scans could play an important role in defining long-term efficacy in subpopulations, such as infants and children. Further steps need to be taken to optimize imaging biomarkers. These steps include establishing standard procedures across multiple research sites, centralized reading centers, and a common scoring system. To validate optimal CT parameter(s), the CF community must continue to collect CT data in phase 1 and 2 trials documenting response to therapeutic intervention. In addition, there is a need for additional longitudinal epidemiology studies to establish the association of CT changes with other outcome measures, such as pulmonary function tests, quality of life measures, and mortality.

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition.

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV(1))/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol-determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height-for age, and weight-for-age-percentiles. The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P > 0.25); after Pa acquisition, the rate of worsening increased significantly (P < 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P < 0.001). The best regression model for predicting change in the FEV(1)/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV(1)/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001). Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV(1)/FVC in detecting early changes in lung disease associated with CF.

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

AbstractAs part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV1)/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol‐determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height‐for age, and weight‐for‐age‐percentiles.The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P &gt; 0.25); after Pa acquisition, the rate of worsening increased significantly (P &lt; 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P &lt; 0.001). The best regression model for predicting change in the FEV1/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV1/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001).Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV1/FVC in detecting early changes in lung disease associated with CF. Pediatr Pulmonol. 2001; 32:277–287. © 2001 Wiley‐Liss, Inc.