James C. Hogg

Hyperpolarized 3He diffusion MRI and histology in pulmonary emphysema.

Diffusion MRI of hyperpolarized 3He shows that the apparent diffusion coefficient (ADC) of 3He gas is highly restricted in the normal lung and becomes nearly unrestricted in severe emphysema. The nature of this restricted diffusion provides information about lung structure; however, no direct comparison with histology in human lungs has been reported. The purpose of this study is to provide information about 3He gas diffusivity in explanted human lungs, and describe the relationship between 3He diffusivity and the surface area to lung volume ratio (SA/V) and mean linear intercept (Lm) measurements—the gold standard for diagnosis of emphysema. Explanted lungs from patients who were undergoing lung transplantation for advanced COPD, and donor lungs that were not used for transplantation were imaged via 3He diffusion MRI. Histological measurements were made on the same specimens after they were frozen in the position of study. There is an inverse correlation between diffusivity and SA/V (and a positive correlation between diffusivity and Lm). An important result is that restricted 3He diffusivity separated normal from emphysematous lung tissue more clearly than the morphometric analyses. This effect may be due to the smaller histologic sampling size compared to the MRI voxel sizes. Magn Reson Med, 2006.

The pathology of asthma

Asthmatics respond with reversible airway narrowing when stimulated in ways that have no effect on non‐asthmatic persons. Studies conducted at the turn of this century established that the pathology present in the airways of asthmatics is based on the inflammatory process. Recent work suggests that this inflammatory response may be driven by a particular group of T cells (Th2 response) that cause an overproduction of IL‐4, IL‐5 and other cytokines that produce an excessive infiltration of eosinophils and overproduction of IgE. The structural changes produced by the inflammatory process result in an overall thickening of the airway wall with changes in the epithelium, an increase in the interstitial matrix particularly the collagen types that contribute to the light microscopic appearance of the basement membrane, the vasculature, smooth muscle and mucous glands. Contraction of airway smooth muscle results in narrowing of the lumen particularly in the bronchioles where smooth muscle surrounds the entire lumen. An increase in wall tissue thickness as a result of asthma amplifies this normal effect producing a greater reduction in the airway lumen. Computer modelling of airway function and direct measurement of airway resistance in patients suggest that the smaller airways are the site of the greatest increase in airway resistance in asthma. These new data have shifted the emphasis away from the concept that abnormal airway smooth muscle function causes asthma toward the hypothesis that inflammatory‐based changes in the airway wall act in series with normal smooth shortening to produce disease. The increased understanding of the role of the inflammatory process provides a basis for treatment of asthma with anti‐inflammatory agents.

What Drives the Peripheral Lung–Remodeling Process in Chronic Obstructive Pulmonary Disease?

The smaller airways (<2 mm in diameter) offer little resistance in normal lungs but become the major site of obstruction in chronic obstructive pulmonary disease (COPD). We examined bronchiolar remodeling in COPD by combining quantitative histology, micro-computed tomography (CT), and gene expression studies. Volumes of bronchiolar tissue, total collagen, collagen-1, and collagen-3 were measured in lung tissue from 52 patients with different levels of COPD severity. Micro-CT was used to measure the number and lumen area of terminal bronchioles in four lungs removed before lung transplantation and in four donor lungs that served as controls. Laser capture microdissection provided 136 paired samples of bronchiolar and surrounding lung tissue from 63 patients and the gene expression of a cluster of tissue repair genes was compared. This study shows that total bronchiolar tissue decreased with progression of COPD and was associated with a reduction in total collagen and relative increase in collagen-3 over collagen-1. The micro-CT studies showed a 10-fold reduction in terminal bronchiolar number and a 100-fold reduction in lumen area. Interestingly, most genes associated with tissue accumulation during repair decreased their expression in both airways and in the surrounding lung as FEV(1) declined, but eight genes previously associated with COPD increased expression in the surrounding lung tissue. Our study shows that small airway remodeling is associated with narrowing and obliteration of the terminal bronchioles that begins before emphysematous destruction in COPD and in relation to differential expression of tissue repair genes in the airways and surrounding lung.

Micro–Computed Tomography Measurements of Peripheral Lung Pathology in Chronic Obstructive Pulmonary Disease

BACKGROUNDnThe smaller airways, < 2 mm in diameter, offer little resistance in normal lungs, but become the major site of obstruction in chronic obstructive pulmonary disease (COPD).nnnOBJECTIVEnTo examine bronchiolar remodeling and alveolar destruction in COPD using micro-computed tomography (micro-CT).nnnMETHODSnMicro-CT was used to measure the number and cross-sectional lumen area of terminal bronchioles (TB) and alveolar mean linear intercept (Lm) in 4 lungs removed from patients with very severe (GOLD-4) COPD and 4 unused donor lungs that served as controls. These lungs were inflated with air to a transpulmonary pressure (P(L)) of 30 cm H(2)O and held at P(L) 10 cm H(2)O while they were frozen solid in liquid nitrogen vapor. A high resolution CT scan was performed on the frozen specimen prior to cutting it into 2-cm thick transverse slices. Representative core samples of lung tissue 2 cm long and 1 cm in diameter cut from each slice were fixed at -80 degrees C in a 1% solution of gluteraldehyde in pure acetone, post-fixed in osmium, critically point dried, and examined by micro-CT.nnnRESULTSnA 10-fold reduction in terminal bronchiolar number and a 100-fold reduction in their minimal cross-sectional lumen area were measured in both emphysematous and non-emphysematous regions of the COPD lungs.nnnCONCLUSIONSnThe centrilobular emphysematous phenotype of COPD is associated with narrowing and obliteration of the terminal bronchioles that begins prior to the onset of emphysematous destruction.

Physiological and immunological effects of chronic antigen exposure in immunized guinea pigs.

Antigenic tolerance was induced in previously sensitized guinea pigs by challenging with ovalbumin (OA) aerosol 1 h/day, 5 days/week for 6 weeks. Reactivity was assessed visually and by lung mechanics. Sera from tolerant and sensitized animals showed comparable titers of antigen-specific antibody by passive cutaneous anaphylaxis with 6-hour, 4-day (heated serum) and 7-day sensitizations. In vitro contractile responses of airway smooth muscle revealed comparable histamine responses in sensitized and tolerant guinea pigs but decreased OA sensitivity in smooth muscle from tolerant animals. Although lung histamine content was equivalent in the two groups, antigen-induced histamine release from chopped lung preparations was significantly less in tolerant animals at a low antigen concentration. We conclude that antigen-induced histamine release is impaired in tolerant animals.

Flow cytometric analysis of defensins in blood and marrow neutrophils.

Abstract: Polymorphonuclear neutrophils (PMN) are vital in host defense against microbial infections. This study provides a flow cytometric method for the quantitative analysis of microbicidal peptides (defensins) in cells of PMN lineage. Rabbit neutrophil peptides, NP‐2 and NP‐5, were measured in all PMN and in subpopulations of PMN expressing l‐selectin. PMN lineage counts were made on Wrights‐stained blood smears and marrow cytospins. Immunoreactivity for NP‐2, and NP‐5 was detected by using the alkaline phosphatase anti‐alkaline phosphatase technique. The results show that marrow PMN express higher levels of NP‐2 and NP‐5 than blood PMN, p<0.001 and that these levels are associated with elevated numbers of myeloid precursors. In both blood and marrow, NP‐2 occurs in two PMN subpopulations and the mean fluorescence intensity of NP‐2 is consistently higher than that of NP‐5. Increased levels of defensins are observed in circulating PMN depicting the most l‐selectin p<0.05. Immunocytochemical results indicate that PMN defensins reside in cytoplasmic granules and are not constitutively expressed on the cell surface. Furthermore, defensins are not detected in monocytes, eosinophils, lymphocytes and erythrocytes. The flow cytometric method described here provides a novel means of quantitating host natural defenses, allows the characterization of PMN subpopulations and has clinical applications.

Molecular mechanisms of sepsis: Molecular biology of the cell

Complex and interrelated biological processes are at work in the expression of the host response to sepsis. To a large degree, these processes reflect drastic changes in the molecular workings of cells of the body. The protean nature of sepsis reflects this molecular adaptation. Studies are continuing to accrue that describe aspects of this process in tissue culture, animal models, and man. However, without an understanding of the basic mechanisms of molecular biology, the understanding of this important and expanding literature is limited. This review describes the basic molecular processes involved in replication of deoxyribonucleic acid (DNA) and transcription of DNA to ribonucleic acid (RNA) in the nucleus, translation of messenger RNA into proteins and the posttranslational modifications of these proteins in the cytoplasm. It uses the process of endotoxin-induced cellular activation as its model and highlights important aspects of DNA promoter and enhancer processes in this activation. Specific examples of known promoter genes and genomic translation are described. This review serves as a primer for the subsequent three review articles in this series that will follow it in preceding issues.

The Prevalence of Common Respiratory Viruses in Human Lungs

n Publisher Summaryn n Viral infections probably initiate a large percentage of childhood and adult asthmatic attacks based on a history of preceding cold, high rates of viral isolation during attacks with lower rates of isolation during symptom-free intervals, and peaks of hospital admissions for asthma coinciding with viral epidemics. Although PCR technology provides a much more sensitive and specific method for detecting viral nucleic acids, its role in diagnosing active viral infection has been only partially explored. The PCR screening procedure for nine common respiratory viruses was performed on lung tissue obtained from both asthmatic and non-asthmatic patients. Six additional cases (four lifetime non-smokers and two with remote minimal smoking histories) were added to control for the fact that both the asthmatics and non-asthmatics smoked heavily. Data from two viruses (the adenovirus and RSV) are used to discuss the possible role of latent and persistent viral infection in the pathogenesis of chronic lung inflammation.n n

Surfactant protein-D deficiency suppresses systemic inflammation and reduces atherosclerosis in ApoE knockout mice

AimsnAlthough surfactant protein-D (SP-D) is a pneumoprotein that is predominantly synthesized by type II epithelial cells in the lung, individuals with increased circulating levels of SP-D are at an elevated risk of mortality from ischemic heart disease. Whether SP-D contributes directly to atherosclerosis is unknown. We determined the effects of SP-D gene deletion in a mouse model of atherosclerosis.nnnMethods and resultsnSP-D knockout (KO) mice were crossed with hyperlipidemic and atherosclerosis-prone apolipoprotein E (ApoE) KO mice to generate SP-D/ApoE double knockout (DKO) mice. Mice were placed on a high-fat diet for 12u2009weeks beginning at 8u2009weeks of age. Compared with ApoE KO mice, SP-D/ApoE DKO mice had significantly less atherosclerosis with reduced macrophage accumulation, decreased local macrophage proliferation, and increased smooth muscle cell coverage in plaques. Interestingly, SP-D deficiency worsened hypercholesterolemia and induced obesity and insulin resistance but suppressed plasma interleukin-6 (IL-6) levels. SP-D deficiency also reduced blood monocytes and neutrophils counts in ApoE KO mice.nnnConclusionnSP-D deficiency reduces atherosclerosis in part by decreasing the accumulation and proliferation of macrophages and by reducing IL-6 levels systemically. SP-D is a promising therapeutic target for cachectic COPD patients with elevated circulating SP-D levels who are at increased risk of cardiovascular morbidity and mortality.

Chapter 6 – Airway Pathology

Publisher Summary nThis chapter reviews the airway pathology as seen in asthma and chronic obstructive pulmonary disease (COPD). The pathology of asthma is dominated by widespread plugging of segmental, subsegmental, and smaller conducting airways, which leads to hyperinflation but not destruction of the parenchyma. In an asthma patient, the airway lumen is filled with an inflammatory exudate that contains plasma proteins, inflammatory cells, sloughed epithelial cells, and mucus. This epithelial sloughing results in metaplastic changes in the epithelium. However, chronic bronchitis of COPD is defined by excess cough with sputum production and is associated with inflammatory processes located in the mucosa, gland ducts, and glands of intermediate sized bronchi between 2 and 4 mm of internal diameter. Thus, the airway obstruction in COPD is the result of an extension of this process to the smaller bronchi and bronchioles under 2 mm internal diameter, which gradually narrows the lumen to cause fixed airway obstruction.