Craig R. Rackley

Building and maintaining the epithelium of the lung

Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.

Airway Epithelial Progenitors Are Region Specific and Show Differential Responses to Bleomycin‐Induced Lung Injury

Mechanisms that regulate regional epithelial cell diversity and pathologic remodeling in airways are poorly understood. We hypothesized that regional differences in cell composition and injury‐related tissue remodeling result from the type and composition of local progenitors. We used surface markers and the spatial expression pattern of an SFTPC‐GFP transgene to subset epithelial progenitors by airway region. Green fluorescent protein (GFP) expression ranged from undetectable to high in a proximal‐to‐distal gradient. GFPhi cells were subdivided by CD24 staining into alveolar (CD24neg) and conducting airway (CD24low) populations. This allowed for the segregation of three types of progenitors displaying distinct clonal behavior in vitro. GFPneg and GFPlow progenitors both yielded lumen containing colonies but displayed transcriptomes reflective of pseudostratified and distal conducting airways, respectively. CD24lowGFPhi progenitors were present in an overlapping distribution with GFPlow progenitors in distal airways, yet expressed lower levels of Sox2 and expanded in culture to yield undifferentiated self‐renewing progeny. Colony‐forming ability was reduced for each progenitor cell type after in vivo bleomycin exposure, but only CD24lowGFPhi progenitors showed robust expansion during tissue remodeling. These data reveal intrinsic differences in the properties of regional progenitors and suggest that their unique responses to tissue damage drive local tissue remodeling. Stem Cells2012;30:1948–1960

Single-breath clinical imaging of hyperpolarized (129)Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition.

We sought to develop and test a clinically feasible 1‐point Dixon, three‐dimensional (3D) radial acquisition strategy to create isotropic 3D MR images of 129Xe in the airspaces, barrier, and red blood cells (RBCs) in a single breath. The approach was evaluated in healthy volunteers and subjects with idiopathic pulmonary fibrosis (IPF).

Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis

Background Assessing functional impairment, therapeutic response and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to red blood cells (RBCs). This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores, and its spatial distribution reflects known physiology and patterns of disease. Methods 13 healthy individuals (33.6±15.7 years) and 12 patients with IPF (66.0±6.4 years) underwent 129Xe MRI to generate three-dimensional quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores, and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung and to detect the known basal and peripheral predominance of disease in IPF. Results 129Xe MRI depicted functional impairment in patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=−0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and subpleural (p<0.01) lung. Conclusions Hyperpolarized129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in patients with IPF, sensitively and non-invasively.

Quantitative analysis of hyperpolarized 129Xe gas transfer MRI

Purpose Hyperpolarized 129Xe magnetic resonance imaging (MRI) using Dixon‐based decomposition enables single‐breath imaging of 129Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129Xe gas transfer to barrier and RBC compartments. Methods A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1H MRI and hyperpolarized 129Xe MRI with one‐point Dixon decomposition to obtain images of 129Xe in airspaces, barrier and red blood cells (RBCs). 129Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). Results In the healthy reference cohort, the mean normalized signals were 0.51 ± 0.19 for ventilation, 4.9 ± 1.5 x 10‐3 for barrier uptake and 2.6 ± 1.0 × 10‐3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. Conclusions This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.

Priming with endotoxin increases acute lung injury in mice by enhancing the severity of lung endothelial injury.

Endotoxin‐induced acute lung injury (ALI) is a commonly used model. However, the effect of a priming dose of endotoxin on lung fluid balance has not been well studied. We hypothesized that endotoxin‐induced ALI in mice would be enhanced under a priming condition. Mice were intratracheally (IT) instilled with either a priming dose of endotoxin from E. coli (0.5 mg/kg) or equal volume of PBS. Eighteen hours later, a larger challenge dose of endotoxin (5 mg/kg) was given IT. Control mice received PBS only. After 24 hr, the mice were sacrificed and the degree of lung injury and inflammation were measured. Endotoxin priming increased body weight loss and worsened hypothermia. Extravascular lung water and lung endothelial permeability were higher in the primed group. Priming with endotoxin reduced alveolar fluid clearance; however, there was no effect on bronchoalveolar lavage (BAL) levels of receptor for advanced glycation end products (RAGE). The primed group had increased alveolar inflammation as demonstrated by increased numbers of neutrophils in the BAL. There was no significant difference in NF‐κB p65 in the lung nuclear extract among the experimental groups. Taken together, priming with a small dose of endotoxin followed by a larger challenge dose of endotoxin induces more systemic illness and increased pulmonary edema in mice, largely due to increased lung endothelial permeability and lung inflammation. This model should be useful to investigators studying ALI who want to simulate the clinical setting in which more than one insult often leads to greater clinical lung injury. Anat Rec, 2010.

Uncovering a third dissolved‐phase 129Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis

The purpose of this work was to accurately characterize the spectral properties of hyperpolarized 129Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers.PURPOSE The purpose of this work was to accurately characterize the spectral properties of hyperpolarized 129 Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers. METHODS Subjects underwent hyperpolarized 129 Xe breath-hold spectroscopy, during which 38 dissolved-phase free induction decays (FIDs) were acquired after reaching steady state (echo time/repetition time = 0.875/50 ms; bandwidth = 8.06 kHz; flip angle≈22 °). FIDs were averaged and then decomposed into multiple spectral components using time-domain curve fitting. The resulting amplitudes, frequencies, line widths, and starting phases of each component were compared among groups using a Mann-Whitney-Wilcoxon U test. RESULTS Three dissolved-phase resonances, consisting of red blood cells (RBCs) and two barrier compartments, were consistently identified in all subjects. In subjects with IPF relative to healthy volunteers, the RBC frequency was 0.70 parts per million (ppm) more negative (P = 0.05), the chemical shift of barrier 2 was 0.6 ppm more negative (P = 0.009), the line widths of both barrier peaks were ∼2 ppm narrower (P < 0.001), and the starting phase of barrier 1 was 20.3 ° higher (P =  0.01). Moreover, the ratio RBC:barriers was reduced by 52.9% in IPF (P < 0.001). CONCLUSIONS The accurate decomposition of 129 Xe spectra not only has merit for developing a global metric of pulmonary function, but also provides necessary insights to optimize phase-sensitive methods for imaging 129 Xe gas transfer. Magn Reson Med 78:1306-1315, 2017.

Managing Respiratory Failure in Obstructive Lung Disease

Exacerbations of obstructive lung disease are common causes of acute respiratory failure. Short-acting bronchodilators and systemic glucocorticoids are the foundation of pharmacologic management. For patients requiring ventilator support, use of noninvasive ventilation reduces the risk of mortality and progression to invasive mechanical ventilation. Challenges associated with invasive ventilation include ventilator dyssynchrony, air trapping, and dynamic hyperinflation. Careful monitoring and adjustment of ventilatory support parameters helps to optimize the patient-ventilator interaction and minimizes the risk of associated morbidity. Extracorporeal life support is an emerging treatment for refractory hypercapnic respiratory failure associated with obstructive lung disease.

Throw Caution to the Wind Instruments

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ATS core curriculum 2015 Part I: Adult pulmonary medicine series editor: Carey Thomson

Gaëtane C. Michaud, Colleen L. Channick, Chad R. Marion, Robert M. Tighe, James A. Town, Andrew M. Luks, Jeremy B. Richards, Sucharita Kher, Prerna Mota, Gina Hong, Natalie E. West, Craig Rackley, Luke Neilans, Josanna Rodriguez-Lopez, Hilary DuBrock, Cassie C. Kennedy, Diana J. Kelm, and Carey C. Thomson Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut; Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Boston, Massachusetts