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This study examines the hypothesis that the cigarette smoke-induced inflammatory process is amplified in severe emphysema and explores the association of this response with latent adenoviral infection. Lung tissue from patients with similar smoking histories and either no (n = 7), mild (n = 7), or severe emphysema (n = 7) was obtained by lung resection. Numbers of polymorphonuclear cells (PMN), macrophages, B cells, CD4, CD8 lymphocytes, and eosinophils present in tissue and airspaces and of epithelial cells expressing adenoviral E1A protein were determined using quantitative techniques. Severe emphysema was associated with an absolute increase in the total number of inflammatory cells in the lung tissue and airspaces. The computed tomography (CT) determined extent of lung destruction was related to the number of cells/m2 surface area by R2 values that ranged from 0.858 (CD8 cells) to 0.483 (B cells) in the tissue and 0.630 (CD4 cells) to 0.198 (B cells) in the airspaces. These changes were associated with a 5- to 40-fold increase in the number of alveolar epithelial cells expressing adenoviral E1A protein in mild and severe disease, respectively. We conclude that cigarette smoke-induced lung inflammation is amplified in severe emphysema and that latent expression of the adenoviral E1A protein expressed by alveolar epithelial cells influenced this amplification process.
Keywords: emphysema; lung inflammation; latent adenoviral infection; cigarette smoking
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The cigarette smoking habit is the major risk factor for emphysema, but only a fraction of the smoking population develops this complication (1). Studies based on autopsy (4, 5), lung resection (3, 6), biopsy (7), and bronchoalveolar lavage (10, 11) have established that all smokers develop peripheral lung inflammation. This process underlies the pathogenesis of emphysema (12), and we postulate that amplification of this cigarette smoke-induced inflammatory response in some individuals accounts for the fact that only a minority of heavy smokers develop emphysema.
Recent studies suggest that latent adenoviral infection (i.e.,
the persistence of adenoviral DNA and protein without replication of a complete virus) is one of the factors that can amplify lung inflammation. The adenovirus targets lung epithelium (13), its DNA persists in higher quantities in lungs of
patients with chronic obstructive pulmonary disease (COPD)
(14), and the adenoviral transactivating protein (E1A) has
been demonstrated in the epithelium of the conducting airways, bronchial glands, and alveolar epithelium (15). Others
have shown that E1A protein expression causes resting cells
to enter the cell cycle (16), that it modulates the cell susceptibility to lysis by tumor necrosis factor-
(TNF-) (17), and
that it increases transcription of host genes by associating with
the DNA binding domains of host transcription factors (18). Transfection of E1A into A549 cells results in excess expression of ICAM-I and interleukin-8 (IL-8) following challenge
(19, 20) and guinea pigs with latent adenoviral infection develop an exaggerated inflammatory response (21) and excess
emphysema when challenged with cigarette smoke (22).
The expression of viral proteins by lung epithelial cells also amplifies the lung inflammatory response through adaptive immune mechanisms. Recent studies show that transgenic mice that express an influenza viral protein in their alveolar epithelial cells develop an epithelial-driven inflammatory response when they are subsequently challenged by adoptive transfer of CD8+ T cells sensitized in vitro to the same viral protein (23, 24). This response is MHC restricted but is independent of the mechanisms used by CD8 cytotoxic T cells to lyse virus-infected cells. As it represents a specific response to epithelial expression of a viral protein expressed in the absence of a lytic viral infection, it may be relevant to the role proposed for latent viral infection in the lung.
The present study was designed to test the hypothesis that the lung inflammatory response is amplified during emphysematous lung destruction using quantitative histological methods to compare lung tissue from heavy smokers with advanced emphysema with lung tissue from patients who had smoked similar amounts but were emphysema free. The same lung tissue was also examined for the expression of adenoviral E1A protein to determine if its expression was related to the amplification of the inflammatory response and the progression of emphysema.
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Patient Population
Tissue from the patients with severe emphysema (n = 7) was obtained by lung volume reduction surgery (LVRS) at the University of Pittsburgh. Lung tissue from the patients with normal lung function and no emphysema (n = 7) and mild emphysema (n = 7) was obtained from lung lobes resected for tumor at St. Paul's Hospital in Vancouver, British Columbia, Canada. All three groups were heavy smokers and had similar age and sex distributions. The procedures used to obtain the tissue were approved by the institutional review boards of both the University of British Columbia and the University of Pittsburgh. All patients signed informed consent allowing their preoperative lung function measurements, CT scans, and resected tissue to be used for the purposes of this study.
Pulmonary Function
The methods used to obtain the measurements of forced expiratory volume (FEV1), subdivisions of lung volume (total lung capacity [TLC], functional residual capacity [FRC], and residual volume [RV]), and diffusing capacity for carbon monoxide (DLCO) reported here met the standard set by the American Thoracic Society and have been described in our previous publications (3, 25).
Morphometric Studies
The severity of the emphysema was determined using a recently described technique where the computed tomography (CT)-determined lung volume is used as the reference volume for the quantitative histology performed on the resected lung tissue. This method has been detailed elsewhere and provides measurements of lung weight and volume in situ as well as estimates of the surface/volume ratio and total surface area of both lungs (26).
The histology was examined by observers who were blinded to all information except that present on the slide. The volume fraction VV of the airspace and the parenchymal tissue surrounding the airspace excluding conducting airways and larger vessels was determined by point counting at 100× magnification and the VV of these spaces taken up by each cell type was determined by point counting at 400× magnification. This process established the volume fraction (VV) of either airspace or tissue taken up by the cell type of interest (29). The total volume of the specifically stained cells was determined by multiplying this histologically determined VV by the CT-determined reference volume of total lung tissue and airspace (29). The number of cells of each type was then determined by dividing the volume of all cells of a particular type by the volume of an individual cell (29). The number of cells present in the tissue and airspace compartments was expressed either as the total number present in the entire lung or as cells/m2 surface area.
Statistics
The data concerning patient demographics, pulmonary function and CT scans (Tables 1 and 2) were analyzed using a one-way analysis of variance. The data for each cell type (Table 3) were analyzed using a single function analysis of variance with a post hoc t test to determine differences between groups (Microsoft Excel). The number of cells present/m2 surface area was related to the percent of the lung occupied by emphysema determined by CT (Figure 1 and Table 4) using a standard curve fitting technique (Cricket Graph, Cricket Software, Malvern, PA).
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RESULTS |
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Table 1 summarizes the data concerning age, sex, smoking history, and lung function for the three groups of patients. The control subjects had smoked amounts similar to those with severe disease and those with mild disease had smoked less than either of the other two groups. The lung function tests show that those who had severe disease had a markedly reduced forced expiratory volume in 1 s (FEV1) (p < 0.005), a reduction in the diffusing capacity (DLCO) (p < 0.005), and an increased RV (p < 0.05) compared with the control subjects and those with mild disease. They also had an increased FRC (p < 0.005) compared with control subjects, but there was no difference in TLC between these three groups.
The data obtained using computed tomography and lung morphometry (Table 2) show that the proportion of the lung taken up by emphysema increased from 1.7 ± 0.4% of the total lung volume in control subjects to 13 ± 2% in mild and 43 ± 4% in severe disease. The combined volume of lung tissue and air was increased (p < 0.05) and lung weight decreased (p < 0.05) when severe emphysema was present. Table 2 also shows that the surface-to-volume ratio of the entire lung decreased in mild (p < 0.05) and further decreased in severe disease (p < 0.0005) compared with control subjects. The total lung surface area, on the other hand, was similar in the control subjects and those with mild disease but was severely reduced in the patients with advanced emphysema (p < 0.0005).
Table 3 shows the total number of inflammatory cells present in the lung in each of the three groups in which severe emphysematous destruction is associated with an absolute increase in polymorphonuclear cells (PMN), macrophages, eosinophils, and CD4 and CD8 cells. Although the CD20 or B cells showed a similar trend, the result was not significant.
Figure 1A shows a photomicrograph of macrophages/monocytes in alveolar tissue and airspaces from one of the patients, and Figure 1B shows the relationship between the number of macrophages present in tissue and airspaces and the percent of the lung occupied by emphysema for all of the patients in the study. This shows a sharp increase in the macrophage number/m2 in the airspaces beginning when approximately 30% of the lung volume is occupied by emphysematous lesions. The number of macrophages in the tissue also increased, but this is not apparent in Figure 1B because the numbers in the tissue are much lower than in the airspaces.
Table 4 shows the data concerning the R2 values for the equation relating the number of each type of cell/m2 surface area and the percentage of the lung taken up by emphysematous destruction. These values ranged from 0.858 (CD8) to 0.483 (CD20) cells in peripheral lung tissue and from 0.630 (CD4) to 0.198 (CD20) in the airspace. These values suggest a strong correlation between the number of inflammatory cells present/m2 surface area and emphysematous destruction of the lung for all cells except the eosinophils and CD20 cells.
Figure 2A shows an example of epithelial cells on the alveolar surface of the lung of a patient with severe emphysema containing E1A protein and Figure 2B shows that there was an approximate 5-fold increase in these E1A-containing epithelial cells in the patients with mild emphysema compared with the control subjects and a 41-fold increase in these cells in the lungs from the patients with severe emphysema. This increase in E1A-containing cells was also associated with an increased expression of ICAM-1 by the lung surface epithelium (Figure 2B).
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DISCUSSION |
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The data reported here show that all of the inflammatory cell types present except the B cells were increased in the lungs of patients with severe emphysema even though these patients had not smoked more than the control subjects. The total number of inflammatory cells present in the lung was used as a measure of the intensity of the inflammatory reaction rather than the cell number per gram lung or square meter of surface area because both lung weight and surface area are reduced by emphysema. The quantitative techniques used in this study are dependent on a random lung sample and might have been artificially increased in tissue obtained by LVRS where the surgeon preferentially samples diseased tissue. To guard against this error, the total number of cells was recalculated using only the volume of emphysematous lung tissue as the reference volume. This correction reduced the reference volume to 43 ± 4% of its original value but still resulted in an increase in the same cell types with similar estimates of significance (data not shown). There was also a relationship between the total amount of emphysematous destruction present on the lung CT scan and the number of each cell type present in the tissue and air spaces/m2 lung surface area. The R2 values of this relationship were above 0.8 for CD4, CD8, and MACS, and 0.749 for PMN in the tissue with slightly lower values for the airspace. Therefore, we conclude that there is an increase in the intensity of the inflammatory response in the lung tissue being destroyed by emphysema, and all of the cells that have been implicated in the pathogenesis of emphysema are present in increased numbers (12, 32).
There was a 5-fold increase in the number of alveolar lung epithelial cells expressing adenoviral E1A protein in mild emphysema and a 41-fold increase in these cells in severe emphysema that paralleled the increase in inflammatory cells in the tissue and airspaces of the lung. This observation is consistent with the hypothesis that a persistent intracellular pathogen such as the adenovirus may be capable of amplifying cigarette smoke-induced inflammation in humans. The adenovirus replicates in type II cells during acute infections and viral DNA and protein persist in the nuclei of lung epithelial cells long after viral replication has stopped (14, 15, 35). Viral DNA also persists in tonsils (36) and peripheral blood lymphocytes (37) following acute lytic infection. The alveolar type II cell targeted by the adenovirus has a cuboidal structure that covers 7% of the alveolar surface area of the normal lung (31). The wide dispersion of these cells and low sensitivity of immunohistochemistry probably account for the small numbers of E1A-positive cells detected in our studies. This result is consistent with studies in an animal model of latent adenoviral infection showing that E1A expression by low numbers of epithelial cells was associated with an amplified cigarette smoke-induced lung inflammation (21, 22, 35).
Walker and coworkers (38, 39) have confirmed the earlier observation of Damiano and coworkers (40) that the PMN enter the alveolar space through the junctions between type I and type II alveolar cells. This places the type II cell at an ideal site to amplify inflammatory cell migration. In vitro studies have shown that a type II-like A549 cell line transfected with E1A produces excess IL-8 and ICAM-1 following challenge (19, 20), and the present study shows there is also excess alveolar surface epithelial cell expression of ICAM-1 in severe emphysema. These data are consistent with the hypothesis that a latent infection of a small number of type II alveolar epithelial cells can amplify the passage of inflammatory cells along their migratory pathway and increase their number in the tissue and airspace. The adenovirus avoids destruction by the host immune response by expressing its E3/19K protein, which binds to host MHC class I protein and lowers the expression of viral antigens on the cell surface preventing recognition by cytotoxic T cells. As the strength of binding between viral E3/19K and host HLA proteins is HLA dependent (41), the genetic makeup of the host could influence the observed difference in E1A expression by host epithelial cells and its effect on the inflammatory process.
The concept that the expression of a viral protein by alveolar epithelial cells in the absence of a replicating viral infection can amplify lung inflammation has received recent support
from studies in transgenic mice (23, 24). These authors developed a transgenic model in which a gene coding for an influenza viral protein was put under the control of a promoter for
the lung surfactant protein gene to create mice that constitutively expressed this viral protein in their alveolar type II epithelial cells. They then showed that adoptive transfer of CD8
lymphocyte clones sensitized in vitro to the same viral protein
produced a remarkable degree of lung inflammation in these
animals. Interestingly, they described a novel response that
was not associated with epithelial destruction by granzymes or
FAS expression, but it was caused by antigen-specific MHC
Class 1-restricted CD8 cells interacting with the epithelial cells.
This interaction involved TNF signaling because recipient mice
lacking the TNF-R1 receptor did not respond. Sensitized CD8+
lymphocytes stimulated the epithelial cells expressing the viral protein in vitro to produce monocyte chemoattractant protein
1 (MCP-1) and the macrophage inflammatory protein (M1P2),
which could account for a very large influx of alveolar macrophages during this response.
These transgenic experiments differ sharply from those reported here in that every type II epithelial cell in the mouse constitutively expresses the protein, whereas only a small fraction of the human alveolar cells express the viral protein. However, they illustrate that an adaptive immune response to a viral protein expressed by the epithelial cells can influence the inflammatory process in the absence of viral replication. We suggest that the increase in expression of adenoviral E1A protein by the lung epithelial cells in the human lungs with severe emphysema reported here may have a similar effect through both an adaptive immune mechanism illustrated by the transgenic experiments (23, 24) and the direct effect of the E1A on ICAM-1 (19) and IL-8 (20) expression. A more complete understanding of the effect of residual intracellular pathogens such as the adenovirus on the host response could shed important light on cigarette smoke-induced inflammation and may explain why only a fraction of heavy smokers develop emphysema.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. James C. Hogg, UBC McDonald Research Laboratories, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: jhogg{at}mrl.ubc.ca
(Received in original form July 27, 2000 and in revised form March 7, 2001).
Dr. Retamales is a Visiting Scientist from the Department of Pathology, Faculty of Medicine, University of Chile, Santiago, Chile. Dr. Coxson is supported by a Canadian Lung Association-Boehringer-Ingelheim Fellowship. Supported by grants from the Medical Research Council of Canada 7246, NIH HLBI, and the George Love Research Fund.This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournal.org
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References |
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REFERENCES
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W. MacNee and K. Donaldson Mechanism of lung injury caused by PM10 and ultrafine particles with special reference to COPD Eur. Respir. J., May 1, 2003; 21(40_suppl): 47S - 51s. [Abstract] [Full Text] [PDF]
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S. Santos, V. I. Peinado, J. Ramirez, J. Morales-Blanhir, R. Bastos, J. Roca, R. Rodriguez-Roisin, and J. A. Barbera Enhanced Expression of Vascular Endothelial Growth Factor in Pulmonary Arteries of Smokers and Patients with Moderate Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1250 - 1256. [Abstract] [Full Text] [PDF]
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R. E. Walter, A. Beiser, R. J. Givelber, G. T. O'Connor, and D. J. Gottlieb Association between Glycemic State and Lung Function: The Framingham Heart Study Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 911 - 916. [Abstract] [Full Text] [PDF]
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P. Boschetto, M. Miniati, D. Miotto, F. Braccioni, E. De Rosa, I. Bononi, A. Papi, M. Saetta, L.M. Fabbri, and C.E. Mapp Predominant emphysema phenotype in chronic obstructive pulmonary disease patients Eur. Respir. J., March 1, 2003; 21(3): 450 - 454. [Abstract] [Full Text] [PDF]
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H. Kanazawa, K. Hirata, and J. Yoshikawa Accelerated Decline of Lung Function in COPD Patients With Chronic Hepatitis C Virus Infection: A Preliminary Study Based on Small Numbers of Patients Chest, February 1, 2003; 123(2): 596 - 599. [Abstract] [Full Text] [PDF]
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T. Fujii, J. C. Hogg, N. Keicho, R. Vincent, S. F. Van Eeden, and S. Hayashi Adenoviral E1A modulates inflammatory mediator expression by lung epithelial cells exposed to PM10 Am J Physiol Lung Cell Mol Physiol, February 1, 2003; 284(2): L290 - L297. [Abstract] [Full Text] [PDF]
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J. J. Atkinson and R. M. Senior Matrix Metalloproteinase-9 in Lung Remodeling Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 12 - 24. [Abstract] [Full Text] [PDF]
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J. H. Vernooy, M. Kucukaycan, J. A. Jacobs, N. H. Chavannes, W. A. Buurman, M. A. Dentener, and E. F. Wouters Local and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease: Soluble Tumor Necrosis Factor Receptors Are Increased in Sputum Am. J. Respir. Crit. Care Med., November 1, 2002; 166(9): 1218 - 1224. [Abstract] [Full Text] [PDF]
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A. Churg, K. Zay, S. Shay, C. Xie, S. D. Shapiro, R. Hendricks, and J. L Wright Acute Cigarette Smoke-Induced Connective Tissue Breakdown Requires both Neutrophils and Macrophage Metalloelastase in Mice Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 368 - 374. [Abstract] [Full Text] [PDF]
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J C Hogg and R M Senior Chronic obstructive pulmonary disease c 2: Pathology and biochemistry of emphysema Thorax, September 1, 2002; 57(9): 830 - 834. [Abstract] [Full Text] [PDF]
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