Pulmonary Function Testing in Idiopathic Interstitial Pneumonias

Martínez, Fernando J.; Flaherty, Kevin R.

doi:10.1513/pats.200602-022tk

Cited by 139 publications

(101 citation statements)

References 76 publications

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“…The lung has traditionally been mechanically characterized non-invasively, for instance using pressure-volume analysis 17 or punch-indentation of whole lungs 19,20 . Invasive methods such as the one described here alter the lung architecture in important ways through the loss of the air-liquid interface that normally exists in the air-filled lung and the loss of pre-stress that maintains lung partial inflation upon relaxation of respiratory muscles.…”

Section: Discussionmentioning

confidence: 99%

Micro-Mechanical Characterization of Lung Tissue Using Atomic Force Microscopy

Liu¹,

Tschumperlin²

2011

JoVE

100

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Matrix stiffness strongly influences growth, differentiation and function of adherent cells [1][2][3] . On the macro scale the stiffness of tissues and organs within the human body span several orders of magnitude 4 . Much less is known about how stiffness varies spatially within tissues, and what the scope and spatial scale of stiffness changes are in disease processes that result in tissue remodeling. To better understand how changes in matrix stiffness contribute to cellular physiology in health and disease, measurements of tissue stiffness obtained at a spatial scale relevant to resident cells are needed. This is particularly true for the lung, a highly compliant and elastic tissue in which matrix remodeling is a prominent feature in diseases such as asthma, emphysema, hypertension and fibrosis. To characterize the local mechanical environment of lung parenchyma at a spatial scale relevant to resident cells, we have developed methods to directly measure the local elastic properties of fresh murine lung tissue using atomic force microscopy (AFM) microindentation. With appropriate choice of AFM indentor, cantilever, and indentation depth, these methods allow measurements of local tissue shear modulus in parallel with phase contrast and fluorescence imaging of the region of interest. Systematic sampling of tissue strips provides maps of tissue mechanical properties that reveal local spatial variations in shear modulus. Correlations between mechanical properties and underlying anatomical and pathological features illustrate how stiffness varies with matrix deposition in fibrosis. These methods can be extended to other soft tissues and disease processes to reveal how local tissue mechanical properties vary across space and disease progression. Video LinkThe video component of this article can be found at https://www.jove.com/video/2911/ Protocol 1. Lung Tissue Strip Preparation 1. Lung tissue is highly compliant and difficult to cut into strips for AFM characterization. To transiently stabilize the lung structure for cutting, inflate isolated mouse lungs intratracheally with 50 ml/kg body weight of 2% low gel point agarose (prepared in PBS) warmed to 37°C. Tie off the trachea and cool the inflated lungs in a bath of PBS at 4°C for 60 minutes. The agarose will gel and stiffen in the airspaces to gently stabilize the lung structure during this interval 5 . Higher agarose concentrations, i.e. 3-4%, may be used to further enhance tissue stabilization for cutting. 2. Cut the agarose-stabilized mouse lung tissue with a razor or scalpel blade into strips of 5 x 5 mm in length and width and 400 μm in thickness, then wash the strips in a PBS bath pre-warmed to 37°C using a 100 ml glass beaker on a bench-top heated stir plate for 5 minutes to remove residual agarose. To exclude large airways and vessels, cut strips from subpleural regions distant from main stem bronchi. If airways and large vessels are to be imaged, cut strips from lung tissue more proximal to main stem bronchi. AFM Microindentation and Fluorescenc...

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Section: Discussionmentioning

confidence: 99%

Micro-Mechanical Characterization of Lung Tissue Using Atomic Force Microscopy

Liu¹,

Tschumperlin²

2011

JoVE

100

View full text Add to dashboard Cite

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“…Individuals with interstitial lung disease (ILD) often have restrictive lung 19 Measurements of lung diffusing capacity (DL CO ) however, have been shown to be the most sensitive in detecting and following restrictive lung defects due to ILD. 20 In our study, most subjects had normal FRCs, near normal TLCs, high RVs and low VC predicted values, a pattern suggesting decreased or impaired expiratory effort; consistent with expiratory muscle weakness rather then a restrictive defect.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary function in adolescents with ataxia telangiectasia

McGrath‐Morrow¹,

Lefton‐Greif²,

Rosquist³

et al. 2007

Pediatric Pulmonology

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Summary. Introduction. Pulmonary complications are common in adolescents with ataxia telangiectasia (A-T), however objective measurements of lung function may be difficult to obtain because of underlying bulbar weakness, tremors, and difficulty coordinating voluntary respiratory maneuvers. To increase the reliability of pulmonary testing, minor adjustments were made to stabilize the head and to minimize leaks in the system. Fifteen A-T adolescents completed lung volume measurements by helium dilution. To assess for reproducibility of spirometry testing, 10 A-T adolescents performed spirometry on three separate occasions. Results. Total lung capacity (TLC) was normal or just mildly decreased in 12/15 adolescents tested. TLC correlated positively with functional residual capacity (FRC), a measurement independent of patient effort (R 2 ¼ 0.71). The majority of individuals had residual volumes (RV) greater than 120% predicted (10/15) and slow vital capacities (VC) less than 70% predicted (9/15). By spirometry, force vital capacity (FVC) and forced expiratory volume in 1 sec (FEV 1 ) values were reproducible in the 10 individuals who underwent testing on three separate occasions (R ¼ 0.97 and 0.96 respectively). Seven of the 10 adolescents had FEV 1 /FVC ratios >90%. Conclusion. Lung volume measurements from A-T adolescents revealed near normal TLC values with increased RV and decreased VC values. These findings indicate a decreased ability to expire to residual volume rather then a restrictive defect. Spirometry was also found to be reproducible in A-T adolescents suggesting that spirometry testing may be useful for tracking changes in pulmonary function over time in this population.

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“…Although a consistently reproducible phenomenon (Figure 3B), the amplitude of decline in pulmonary collagen level in the combined model compared with bleomycin alone is admittedly relatively modest, constituting 33.4 Ϯ 3.9% of the normal collagen content. However, it is important to consider that fibrosis correlates with decline in lung function, 36 and that a therapy resulting in only 3% higher forced vital capacity than placebo is now being celebrated as a significant achievement in treating patients with scleroderma lung disease. 37 Our observation suggests that there might be potential for further enhancing the antifibrotic regulation in the lungs by therapeutically manipulating the local pulmonary milieu and/or the phenotypes of infiltrating T lymphocytes.…”

mentioning

confidence: 99%

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

Pochetuhen

Luzina

Lockatell

et al. 2007

The American Journal of Pathology

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Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-␣, interferon-␥, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-␤1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-␣, interferon-␥, and active transforming growth factor-␤1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu. (Am J Pathol

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Pulmonary Function Testing in Idiopathic Interstitial Pneumonias

Cited by 139 publications

References 76 publications

Micro-Mechanical Characterization of Lung Tissue Using Atomic Force Microscopy

Micro-Mechanical Characterization of Lung Tissue Using Atomic Force Microscopy

Pulmonary function in adolescents with ataxia telangiectasia

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

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