Immunohistochemical Analysis of Mastocyte Inflammation: A Comparative Study in COPD Associated with Tobacco Smoking and Wood Smoke Exposure

doi:10.21203/rs.3.rs-5124454/v1

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Immunohistochemical Analysis of Mastocyte Inflammation: A Comparative Study in COPD Associated with Tobacco Smoking and Wood Smoke Exposure

https://doi.org/10.21203/rs.3.rs-5124454/v1

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Chronic Obstructive Pulmonary Disease (COPD) exhibits some phenotypic differences between patients with biomass smoke inhalation (COPD-B) and tobacco smoking (COPD-T), as COPD-B is characterized by less emphysema but more airway disease and vascular pulmonary remodeling; these characteristics were related for mast cells in lung tissues for COPD-T. Our objective was to characterize the differences between the number of mast cells in COPD-B and COPD-T patients.

METHODS: A cross-sectional study was conducted on lung tissue resections for suspected cancer obtained between 2014 and 2021 from patients with documented COPD due to wood smoke or tobacco exposure. Histological samples were analyzed for mast cell count, CD34 + expression, and structural changes in the lung tissue and pulmonary circulation.

RESULTS: 20 histological samples were analyzed, with significant differences found in mast cell count [median 8 (p25-75, 5–11) vs 2 (p75-25, 0–6), p = 0.016) and severe peribronchiolar fibrosis (60% vs 10%, p = 0.04) between COPD-B and COPD-T patients. A positive correlation (spearman rho = 0.879, p > 0.001) was observed between mast cell count and a gradual increase in pulmonary artery diameter.

CONCLUSION: Compared with COPD-T, patients with COPD-B exhibit more counts of mast cells in lung tissue and peribronchiolar fibrosis than tobacco smoke-exposed patients, suggesting a pathogenic role of mast cells in COPD-B more than in COPD-T.

Mast Cells

Airway Diseases

COPD biomass

Wood Smoke

Tobacco Smoking

Phenotypic Differences

Immunohistochemistry

Chronic obstructive pulmonary disease (COPD) is characterized by an inflammatory process induced by noxious particles or gases that can activate the cascade of inflammatory reactions leading to tissue destruction in the airways (1, 2). The toxic particles from cigarette smoke damage the airway epithelium, with the most prominent changes being the shortening of cilia, epithelial metaplasia, and hyperplasia of goblet cells (3).

Most of the evidence on the mechanisms of damage induced by inhaled agents that cause COPD is based on the COPD study due to tobacco smoke (COPD-T); however, phenotypic differences have been documented between exposure to tobacco smoke. biomass (COPD-B) and smoking (4.5). The prevalence of the Th2 inflammatory phenotype in COPD-B describes higher levels of sputum eosinophils, serum eosinophils, or FENO (5–7).

Women exposed to HL present more peribronchiolar scarring and small airway disease (8–10). In addition to these differences, greater pulmonary circulation and pulmonary hypertension remodeling have been documented (11, 12); in various histological studies, this evidence seems consistent (8, 11, 13). These differences have suggested the existence of two different COPD phenotypes, one related to tobacco smoke and the other to biomass.

Inflammation associated with mast cells has shown infiltration of the small airway with a change in the connective tissue/mucosa balance, relating to hyperreactivity to the airway (14) and an increase in the density of perivascular mast cells with an increase in endothelial growth factor (VEGF) and association with pulmonary hypertension (15, 16). In this sense, the pulmonary vascular endothelium is involved in vascular remodeling in pulmonary hypertension, which can be influenced by proangiogenic endothelial progenitors derived from the CD34 + CD133 + bone marrow (17). Its increase has been correlated with pulmonary artery pressure. (18) and its expression demonstrated in the endothelium of patients with PH.

Our objective was to characterize the differences between the number of mast cells in COPD-B and COPD-T patients, evaluate whether there is any relationship between the number of mast cells and the largest diameter of the pulmonary artery by tomography, and determine the expression of CD34 + in pulmonary microvasculature.

Design and selection of histological samples.

It is a cross-sectional study carried out at the National Institute of Respiratory Diseases, It is a referral center in Mexico for the care of respiratory diseases. This study was submitted to and approved by the local ethics committee under number C50-22. A series of surgical resections of lung parenchyma obtained between 2014 and 2021 from the pathological anatomy file were subjected to pathological review. We emphasize that the patients were not subjected to any procedures for this study; only histological material from the pathology department was reviewed. These histological samples were examined; the main indications for resections were in patients with a primary nodule suspicion of cancer and, secondarily, segmental or lobar resections for hemoptysis. The selection criteria for the analysis of the samples were patients over 40 years of age with a record of COPD due to wood smoke or smoking in the clinical record or those who had a cumulative exposure to wood smoke greater than 200 hours (19), or tobacco consumption > 10 pack-years (20). Samples from patients who received inhaled or systemic steroids 30 days before taking the biopsy, patients with records of active infectious processes corroborated by cultures or visualization of the parenchyma, or suspected interstitial lung disease were excluded. In parallel, the clinical information of the patients was reviewed, obtaining demographic data, medical history, respiratory function, especially spirometry with bronchodilator (FEV1/FVC, FEV1, FVC) and tomographic measurement of the diameter of the pulmonary artery was performed. Samples from patients receiving inhaled or systemic steroids were excluded.

Tissue procurement and processing.

The histological samples of the selected patients were reviewed. For the latter, it was ensured that the lung parenchyma was free of malignant cells. During the histological review of the sections stained with H-E, it was ensured that they presented sufficient and optimal material for evaluation; two pathologists reviewed all slides.

Immunohistochemistry (IHC) was performed on the paraffin blocks of the selected cases in 3 µm histological sections, with mouse monoclonal anti-human chymase antibodies (Mouse Monoclonal Mast Cell Chymase antibody-abcam, ab2377, dilution 1/100), murine recipient. To determine the positivity of the samples, they were contrasted with the tissue controls suggested by the manufacturer (esophagus and brain).

Definition of lung regions and morphometric analysis

One to five peripheral airways were evaluated in 10 fields at 40x for each case. The variables evaluated in the respiratory tract were: 1) epithelium, 2) peribronchiolar subepithelial area, and 3) smooth muscle.

Peripheral airways were defined as airways with a circumferential size of ≤ 6 mm to > 2mm, and small airways were defined as smaller than ≤ 2mm.

Measurements by pathologists.

The IHC reactions were analyzed at 40x in 10 high-power fields in a digital pathology scanner (Aperio CS2 for Digital Preparations), creating files on this equipment for each selected case and the antibody made. The first pathologist selected each field, and the second pathologist used the same fields. None of the pathologists knew the count of the previous one to guarantee blinding and repeatability.

The histological samples were analyzed semi-quantitatively, defining the intensity of changes using crosses on a visual scale from 0 to 3 according to the grades (0 absent, 1 + Mild, 2 + moderate, 3 + intense). The changes found in patients with COPD-T and COPD-B were reported as:

Inflammation is the inflammatory infiltrate of lymphocytes on the airway wall.

Peribronchiolar fibrosis: defined as the amount of fibroconnective tissue deposited in the wall of the airway

Goblet cell metaplasia: defined as the replacement of a mature epithelial cell by another mature cell different from the original

Intensity of the affinity of anti-Cd34 + for the microvascular endothelium.

A single pathologist counted mast cells marked by CC1 in the peribronchial region of the small airway. The pathologist performed two measurements, separated by a range of 14 days, and averaged them to produce a repeatable measurement.

Statistic analysis.

Differences between groups were analyzed using Chi-Square or Mann-Whitney U tests, paired analyses within groups using Wilcoxon rank sum tests, and correlations between cell concentrations and lung function using the Spearman rank correlation coefficient. Two-tailed p values <0.05 will be considered significant. To analyze the repeatability of the results, agreement was calculated using the Kappa coefficient for the categorical measurements, and a Band Altmann analysis was performed for the mast cell count.

Statistical analysis was performed using Stata 17.1 software.

A total of 118 histological samples from patients exposed to wood smoke or tobacco smoke. Ninety-two samples were discarded due to insufficient lung tissue, bronchoscopy biopsy, tumor infiltration, or data of granulomatous inflammation; two samples were excluded due to an insufficient exposure index, and two samples were excluded because the patient recently had received antibiotics.

The main demographic characteristics are that women predominate in the COPD-B group, there were no differences in comorbidities, and the main cause of lung resection was confirmed lung cancer. There were no differences in lung function or peripheral eosinophils. (SEE TABLE1). For the qualitative measurements of the airway between the two pathologists, a Kappa coefficient greater than 0.7 and statistically significant agreements > 80% were found (Table 2).

Table 1

Demography and clinical characteristics.
	COPD- Biomass (n = 10)	COPD-TOBACO (n = 10)	P value
Female, n ^¥	8	1	0.003
Age, median (p25-75)*	63 (46–78)	68.5 (55–76)	0.382
Pack-years, median (p25-75)*	-	45 (37.5–68)	-
Hours-years biomass exposure, median (p25-75)	238 (180–308)	-	-
Diabetes, n^¥	4	2	0.314
Previous COPD diagnosis, n	7	9	0.291
Arterial hypertension, n ^¥	5	5	0.672
Ischemic Heart disease, n ^¥	1	5	0.070
Lung cancer biopsy, n ^¥	7	6	0.5
Nonspecific inflammation biopsy, n^¥	4	5	0.5
FEV1/FVC, median (p25-75)*	0.53 (0.47-.63)	0.61 (0.55-.87)	0.158
FEV1L, median (p25-75)*	1.02 (0.97–1.31)	1.8 (0.88–2.58)	0.408
FEV1p, median (p25-75)*	60 (49–75)	65 (39–78)	0.796
FVCL, median (p25-75)*	2.01 (1.9–2.1)	2.66 (1.4–4.2)	0.814
FVCp, median (p25-75)*	75 (64–89)	78.5 (45–101)	0.10
Pulmonary diameter (mm), median (p25-75)*	27.9 (25.2–29.8)	24.9 (23.3–29.4)	0.143
¥ Fisher’s test; *U Mann Whitney test.
Abbreviations: COPD, chronic obstructive pulmonary disease; p25-75, 25th to 75th percentile; FEV1, Forced Expiratory Volume in the first second; FVC, Forced Vital Capacity; mm, millimeters.

Table 2

Semiquantitative scale, Cohen’s Kappa Concordance Among Pathologists.
	Kappa coefficient	Agreement (%)
Small airway inflammation*	0.869	90
Peribronchiolar fibrosis*	0.771	85
Pigment Deposit*	0.921	95
Smooth muscle hyperplasia*	0.773	85
Goblet cell metaplasia*	0.855	95
Microvascular Intensity of CD 34+*	0.719	80
*Statical significance p > 0.001

For quantitative cellular measurements, 20 observations without missing data were reported. Measurement 1 (M1) was 6.1 (95% CI 2.3–9.9). The mean for measurement 2 (M2) was 6 (95% CI 2-9.2). Bland-Altman analysis showed a mean bias of 0.1. The limits of agreement were − 4.73 cells for the lower limit and 4.36 cells for the upper limit. There was 1 case (5.00%) that exceeded the upper limit; Lin's coefficient of agreement corresponds to 0.958 (FIGURE 1).

The main differences between patients exposed to biomass are peribronchiolar fibrosis and a greater number of mast cells in COPD-B, which are statistically significant (Table 3).

Table 3

Histological futures for the semiquantitative report and quantitative cell count for mast cell.
	COPD- Biomass (n = 10)	COPD-TOBACCO (n = 10)
Small airway inflammation^∂
Mild +	5	4
Moderate ++	4	5
Severe +++	1	1
Peribronchiolar fibrosis
Absent -	0	3
Mild+	4	6
Moderate++ ^ẞ	6	1
Pigment Deposit^∂
Mild +	6	5
Moderate ++	3	3
Severe +++	1	2
Smooth muscle hyperplasia^∂
Absent -	1	3
Mild +	0	2
Moderate ++	6	4
Severe +++	3	1
Goblet cell metaplasia ^∂
Absent-	1	3
Mild +	0	2
Moderate ++	6	4
Severe +++	3	1
Microvascular Intensity of CD 34+ ^∂
Absent-	0	2
Mild +	2	4
Moderate ++	4	3
Severe +++	4	1
Count Mast cell, median (p75-25) ‡	8 (5–11)	2 (0–6)
Statistical analysis: for categorical variables, the Fisher’s test was applied ^ẞ p = 0.029, ∂ p > 0.05 for continuous variables. ‡ The Mann-Whitney test was applied = 0.0165.
The intensity of each qualitative characteristic evaluated by the pathologists was expressed using a visual analog scale ranging from "-" indicating the absence of the finding, "+" for mild intensity, "++" for moderate, and "+++" for intense.

Figure 3 shows a positive correlation between the number of mast cells and the gradual increase in the diameter of the pulmonary artery measured by tomography.

Figure 4 highlights the greater number of mast cell cells and the intensity of the expression of the microvascular endothelium of the anti-CD34 + antibody, as well as the greater number of mast cells according to smooth muscle hyperplasia, with statistically significant differences (p > 0.05) in these characteristics.

This pilot analysis identified a difference in the content of total mast cell counts in patients with COPD-B, greater expression of CD34 + in the vascular endothelium, and peribronchiolar fibrosis. Furthermore, a positive correlation was found in the diameter of the pulmonary artery and the total number of mast cells. In addition to finding a trend of greater smooth muscle hyperplasia and the intensity of CD34 + in the endothelium of the pulmonary circulation and the number of mast cells.

These findings may explain some of the known differences between COPD-T and COPD-B. For example, they can explain the tendency of inflammation related to small airway disease (9) and eosinophilic inflammation resistant to response to steroid treatment, as shown by Salvi et al (5). For example, Amir Soltani et al. have described hyper-reactivity to the airways and the presence of mast cells in the airways in patients with COPD(14), in addition to less severe obstruction in patients with COPD-T with a greater number of mast cells(15); Both phenomena have been identified in patients exposed to wood smoke (21–23) and in our study could explain the relationship with smooth muscle remodeling and hyperplasia. The presence of mast cells may be mediated by an intricate stimulation of pro-Th2 and Th17 cytokines and various epigenetic mechanisms described in some COPD-B patients (24). Mast cells have been described as a key cell that can accompany a Th2 response, respond to steroids, or be associated with peripheral eosinophilia (25, 26); however, another phenotype with migration to the submucosal and connective tissue compartments has also been described. by non-Th2-IgE interleukins (27), especially TNFa, IL-8, IL-1b, IL17R, and inflammasome activation (28, 29), which in turn have been identified as predominant cytokines in COPD-B(24, 30, 31)

On the other hand, multiple reports have indicated that mast cells may be involved in vascular remodeling and angiogenesis and be associated with pulmonary hypertension in patients with COPD(14, 16). In this sense, local recruitment in different compartments and expressions of inflammatory phenotypes in tissues influenced by cytokines of adaptive immunity are of particular importance (32), providing long life to the cell and locating them mainly in the small airway and connective tissues. (33). Mast cells are regulators of angiogenesis through the production of vascular endothelial growth factor (VEGF), angiotensin II, and the release of proangiogenic proteases (14, 16).

The CD34 + molecule has been described as having greater expression in the endothelium of patients with pulmonary hypertension (18); in addition to this, it has also been related to mast cell migration (34). What makes mast cells particularly interesting is that they degranulate in hypoxic conditions, which in turn causes an imbalance in ROS and nitric oxide (35–37). As described in different cohorts, patients with COPD-B show this characteristic (38, 39).

This pilot study lacks a control group due to the complexity of obtaining healthy lung tissues in a purely respiratory center. Most of the tissues obtained were derived from patients with suspected cancer, and although the diseased tissue was discarded, it was ensured that there were no malignant cells or changes associated with them, and the tumor microenvironment could influence the findings. In addition, the measurements made by the pathologists were repeatable and reproducible, and our findings are consistent with similar work in patients with COPD-T, but it seems especially relevant that mast cells may be a key cell that allows us to better understand the differences between COPD-T and COPD-B, so we consider that these first findings show the relevance of continuing with this avenue of research and addressing problems related to mast cell signaling in COPD-B.

In conclusion, samples from patients with COPD-B presented a higher mast cell count, peribronchiolar fibrosis, and expression of CD 34 + in the vascular endothelium than those from tobacco smokers. Mast cell count was positively correlated with pulmonary artery diameter measured by chest tomography. Mast cell inflammation may explain some of the differences between COPD-B and COPD-T.

Ethics approval and consent to participate: The local ethics committee approved the study (C54-22). This study received an exemption of informed consent. It is an observational study in which biopsies performed for reasons other than this study were studied.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests: The authors report no conflicts of interest in this work.

Funding: Instituto Nacional de Enfermedades Respiratorias funded the study, and the Chamber of Deputies of Mexico participated in a program for COP-B in women.

Authors' Contributions: RMR, RRH, and RPP contributed equally to the study's conception and design, data acquisition design, analysis, data interpretation, drafting of the article, and critical revision of significant intellectual content. MPP, MCMG, and ABT also contributed equally to data acquisition and reviewed the clinical content. GICS participated in understanding and critical revision of substantial intellectual content and prepare figure 4. DMQC and RMR reviewed the histological tissues and selected the biological material.

Acknowledgement

Instituto Nacional de Enfermedades Respiratorias funded the study, and the Chamber of Deputies of Mexico participated in a program for COP-B in women.

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Immunohistochemical Analysis of Mastocyte Inflammation: A Comparative Study in COPD Associated with Tobacco Smoking and Wood Smoke Exposure

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Abstract

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INTRODUCTION

MATERIALS AND METHODS

Definition of lung regions and morphometric analysis

RESULTS

DISCUSSION

Declarations

Acknowledgement

References

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