Scientifica

Scientifica / 2014 / Article

Research Article | Open Access

Volume 2014 |Article ID 613689 | 9 pages | https://doi.org/10.1155/2014/613689

Gender Differences in Pulmonary Function, Respiratory Symptoms, and Macrophage Proteomics among HIV-Infected Smokers

Academic Editor: P. Borger
Received01 Dec 2013
Accepted23 Jan 2014
Published04 Mar 2014

Abstract

Background. HIV-infected subjects have an increased incidence of pulmonary emphysema. There are known gender differences in COPD phenotypic expression and diagnosis, but this is not well characterized in lung disease related to HIV. We analyzed a group at risk for the development of COPD (HIV-infected smokers) to determine gender differences in pulmonary symptoms, pulmonary function tests, and HRCT appearances. Methods. This was a cross-sectional, baseline analysis of a prospective study performed between 2006 and 2010. We performed symptomatic, pulmonary function, and computed tomography assessments in 243 HIV-infected smokers. In a subset bronchoalveolar lavage was performed with proteomic analysis of their alveolar macrophages. Results. The majority of the participants were male 213 (87.6%). There was significantly higher percentage of cough and phlegm production in males. There was also a lower FEV1 and a higher RV in males than females. Proteomic analysis revealed 29 proteins with at least a 2-fold higher expression in males and 13 identified proteins that were higher in females. Conclusions. In this group of HIV-infected smokers, airway symptoms and pulmonary function test abnormalities were higher in men than women. These gender differences may be due to differential expression of certain proteins in this group.

1. Introduction

The prevalence of chronic obstructive pulmonary disease (COPD) is increasing dramatically in women. In fact, COPD now kills more women than breast and lung cancer combined [1] and the number of new cases of COPD is increasing three times as fast in women annually as compared to men [2]. Data suggests that there are differences in the presentation and phenotypic expression of COPD in women compared to men [3], While women may be more susceptible to early onset COPD, there appears to be a gender bias in the diagnosis of COPD, with women less likely to be diagnosed than men with similar symptoms [4, 5].

Human immunodeficiency virus (HIV) has emerged as an independent risk factor for COPD in smokers, as data in the pre- and postantiretroviral (ART) era demonstrate increased susceptibility to cigarette smoke and a high percentage develop abnormalities in lung function, including loss of diffusing capacity and irreversible air-flow obstruction [6, 7]. As ART has transformed HIV into a chronic disease, noninfectious pulmonary comorbidities are assuming greater importance for this population [8]. Whether cigarette smoking affects HIV-infected women differently than men has not been systematically studied.

The purpose of the current study was to compare respiratory symptoms, lung function, and results of high resolution computed tomography (HRCT) scanning among HIV-infected women and men. While previous studies have defined phenotypic differences between men and women in advanced COPD in the general population [4, 5], we were interested in studying an at risk group of smokers at an earlier disease stage. In addition, we examined alveolar macrophage proteomics in a subgroup of males and females. We wished to determine whether differences in protein expression existed between the two groups and whether such differences could provide mechanistic insight into observed symptomatic and physiologic differences.

2. Materials and Methods

This was a cross-sectional, baseline analysis of a prospective study performed between 2006 and 2010. The study involved the longitudinal assessment of the pulmonary status of HIV-infected subjects () and included symptomatic, pulmonary function, and computed tomography assessment. In addition, a subset of agreeable subjects underwent bronchoalveolar lavage followed with proteomic analysis of their alveolar macrophages. The study was approved by the Ohio State University institutional review board (Biomedical Sciences IRB number 2005H0197) and all subjects signed informed consent. For the purposes of this analysis, only participants who had a history of cigarette smoking were included ().

2.1. Respiratory Symptoms

All subjects answered questions related to the presence or absence of respiratory symptoms, specifically, shortness of breath, cough, phlegm production, and wheezing.

2.2. Pulmonary Function Studies

All participants underwent complete pulmonary function testing, including spirometry, as well as measurement of lung volumes and carbon monoxide diffusing capacity according to American Thoracic Society guidelines. Predicted equations for spirometry were those of Goldman [9], lung volumes Crapo [10], and diffusing capacity Miller [11].

2.3. Computed Tomography of the Chest

All subjects underwent HRCT (high resolution computed tomography) of the chest. Scans were performed on a Siemens multislice CT scanner (16-slice, 20-slice open CT, or 64-slice), without IV contrast. Inspiratory and expiratory images were performed. All scans were read by an experienced chest radiologist. The presence or absence of emphysema (bullae, thin-walled cystic spaces, or abnormal decreases in attenuation accompanied by vascular disruption) was recorded, as was the presence of bronchial dilatation, bronchial wall thickening, and air trapping as previously described [12].

2.4. Alveolar Macrophage (AM) Proteomics

To examine alveolar macrophage proteomics, we matched 6 female subjects with 6 male subjects of similar age, smoking history, and use of ART. Briefly, a bronchoalveolar lavage (BAL) in the right middle lobe was performed to obtain a lavage sample of approximately 50 mL for the isolation of AMs [13]. After obtaining BAL, an initial centrifugation was performed to spin down AMs. AM purity in each cell preparation was evaluated by light microscopic examination of diff-quick cytospins to ensure at least 90% purity. After preparation of AMs, a small aliquot of AM cells was suspended in RIPA buffer for protein concentration measurement using BCA protein assay [14]. Afterwards, AMs obtained from each participant were lysed at a density of 3–5 × 106 cells/mL in 2D gel cell lysis buffer [13] and frozen at –80°C for 2D gel proteomic analysis performed in batches.

For first dimension electrophoresis, 100 μL cell lysates (~2 mg cellular proteins) were mixed with 400 mL rehydration buffer and spun at 14,000 g, at 4°C for 10 minutes. Four hundred fifty μL of the supernatant was then subjected to first D electrophoresis overnight on an Amersham IPGphor using premade 24 cm IPG strips. Following first D electrophoresis, the strip was equilibrated in a buffer containing for 10 min. at room temperature. This is followed by a second equilibration for 10 min. Second dimension electrophoresis was run on a 20 × 24 cm SDS-PAGE on an Amersham Dalt II, a large format (20 × 24 cm) 2D gel system. Under this condition, a total of approximately 1,100–1,500 protein spots were detected and analyzed in each AM sample.

After 2D electrophoresis, the gels were fixed and stained with SyproRuby fluorescence dye according to manufacturer’s protocol. Gel images were captured on a Typhoon 9200 laser scanner (Amersham) that offers high resolution and quantification of protein spots. Protein quantification on all 2D gels was performed using ImageMaster 2D software (Nonlinear Dynamics) [13, 15, 16]. Proteins demonstrating significant and reproducible differences between male and female HIV smokers were subjected to protein identity determination using tandem mass spectrometry at OSU’s Proteomic Shared Core Facility.

2.5. Statistical Analysis

The prevalence of respiratory symptoms, findings on high resolution chest CT, and pulmonary function testing were analyzed using linear/logistic models with sex, age, pack-years smoking history, viral load, BMI, and IV drug use as covariates. Because of skewness in the data, log transformation was performed on pack-years smoking history, residual volume, BMI, and viral load before model fitting.

3. Results

3.1. Participants

Table 1 demonstrates the baseline characteristics of the study population. The sex distribution and demographics of the population were similar to that of the HIV demographics of Central Ohio 30 females (12.3%) and 213 males (87.6%). The mean age of the participants was 44.3 with 57.6% Caucasians, 40.7% African Americans, and 1.7% other. The average pack-year history of the group was 19; 63% of females and 65% of males were current smokers. The average viral load was 36,552 with an average CD4 count of 474.


DemographicsAll subjects

Subject number243
Male number (%)213 (87.6%)
Female number (%)30 (12.3%)
Age, mean (std dev)44.3 (8.4)
BMI, mean (std dev)26.98 (8.35)
Race
 Caucasian (%)40.7
 African American (%)57.6
 Other (%)1.7
IV drug use number (%) 43 (17.7%)
Current smokers number (%)157 (64.6%)
 Pack years, mean (std dev)
CD4 count, mean (std dev)
Viral load, mean (std dev)

3.2. Respiratory Symptoms, Pulmonary Function Testing, and Radiographic Imaging

Table 2 demonstrates clinical pulmonary findings among the subjects according to participant gender. Males had a significantly higher prevalence of cough (72.8% versus 51.7% ()) and phlegm production (71.2% versus 51.7% ()) compared to females. There was no statistically significant differences between males and females with regard to shortness of breath (32.4% males versus 44.8% females ()) and wheezing (49.8% males versus 55.2% females ()).


Male Female Odds ratio/regression coefficient value

Symptoms
 Cough (%)72.851.74.330.0015
 Phlegm (%)71.251.72.680.025
 Shortness of breath (%)32.444.81.080.87
 Wheeze (%)49.855.21.060.89
CT chest findings
 Emphysema (%)45.833.31.510.39
 Bronchial dilatation (%)22.216.61.210.73
 Air trapping (%)29.122.22.620.083
 Bronchial wall thickening (%)16.513.31.110.86
Pulmonary function testing
 FEV1/FVC76.378.3−1.480.40
 FEV1% predicted91.497.3−8.350.0086
 RV% predicted115.199.40.116*0.0496
 TLC% predicted103.599.82.570.42
 DLCO% predicted79.975.54.350.19

The regression coefficient for RV% predicted is in the log scale.

A comparison of the HRCT findings did not reveal any differences regarding the prevalence of emphysema, bronchial dilatation, or bronchial wall thickening. Although there was no statistically significant difference in the prevalence of air trapping, there was a trend towards significance (29.1% males versus 22.2% females ()).

Based on pulmonary function testing, males had a lower percent predicted forced expiratory volume in one second (FEV1). The average FEV1 percent predicted was 91.4% in males versus 97.3% in females (). There was also a higher prevalence of air trapping as measured by the residual volume (RV) in males compared to females with an average RV of 115.1% in males compared to 99.41% in females (). While there was no significant difference between males and females with regard to diffusion impairment, both groups exhibited diffusion impairment with a mean diffusing capacity for carbon monoxide (DLCO) of less than 80% predicted in both groups (79.9% in males and 75.5% in females).

3.3. Proteomic Analysis

Table 3 demonstrates the subset of subjects that underwent BAL and proteomic analysis. There were 6 men and 6 women who were matched for HAART therapy, smoking status and pack years, age and race. Tables 4 and 5 demonstrate results of 2D gel alveolar macrophage proteomic analysis between men and women. Sixty-five proteins were identified that were at least twofold greater in men of which 29 were identified (Table 4). Thirty-eight proteins were identified that were at least twofold greater in women of which 13 were identified (Table 5).


GenderHAARTCurrent smokerPack yearsAgeRace

FYN137W
FYY3147W
FYY1648B
FYY647B
FYY1133W
FYY2852W
MYN150W
MYY3642W
MYY1144B
MYY1151B
MYY1434W
MYY2945W


Spot
number
Mean of normalized
volume of male
Mean of normalized
volume of female
Fold changes
(male/female)
Accession number
(Swiss-Prot)
Protein IDMowse
score
Observed pI/Mr
(KDr)
Number of peptides
by MS/MS
Total seq.
coverage (%)

8670.048670.020832.34NP_006079Tubulin, beta, 221035.0/53.3862
10090.056500.021672.61BAD96752Beta-actin variant4717.5/45.1831
13180.126000.029834.22P11177Pyruvate dehydrogenase E1 component subunit beta, mitochondrial4276.2/39.6439
17730.220830.062173.55NP_001900Cathepsin D preproprotein8985.2/27.7533
18020.062000.030672.02P30041Peroxiredoxin 6 3646.0/27.4776
18720.050170.016003.14P25787Proteasome subunit alpha type 22656.6/25.7676
30740.172170.073502.341IVY_AChain A, Physiological Dimer Hpp Precursor2304.5/29.439
31570.066000.032502.03P05092Cyclophilin A2066.4/16.4352
32350.119670.0105011.40P1102178 kDa glucose-regulated protein21935.3/74.92450
48800.095500.0056716.85CAA68491 Glutathione peroxidase11435.5/23.6489
49250.128670.00100128.67P26447Protein S100-A42085.9/11.9545
49900.118670.019336.14P00558Phosphoglycerate kinase 120117.9/44.91372
51730.111330.034503.23P30048Thioredoxin-dependent peroxide reductase, mitochondrial2047.7/28.0316
51800.100500.033003.05Q06830Peroxiredoxin-16367.3/22.2747
88490.068500.0010068.50P54727UV excision repair protein RAD23 homolog B6434.8/43.2841
88720.059330.025332.34P06576ATP synthase subunit beta, mitochondrial5135.3/56.5834
89850.092330.019004.86P06733Enolase 16385.7/42.3828
90030.158000.030335.21AAA51580Gamma-actin6204.6/43.3319
90230.634830.280002.27 Q3ZCM7Tubulin beta-8 chain3444.8/49.7418
91030.051330.018502.77 P06396Gelsolin12415.9/85.6425
91260.067170.011006.11O953366-phosphogluconolactonase3315.7/27.8439
91410.108670.034003.201HJO_AChain A, Heat-Shock 70 kd Protein 42 kd Atpase N-Terminal Domain13297.4/28.6545
91520.085830.0021739.62P09668Procathepsin H5178.4/37.4329
91530.134330.014009.60P52566Rho GDP-dissociation inhibitor 26165.1/23.01075
91690.097330.046332.10AAA35607IgE-binding protein2577.4/26.1222
93370.103170.041832.471GLO_A Chain A, Crystal Structure Of Cys25ser Mutant Of Human Cathepsin S1936.6/16.5532
94080.298330.126832.351AWI_AChain A, Human Platelet Profilin complexed with The L-Pro10 Peptide9889.1/14.5293
95042.499501.100672.27P08670Vimentin25415.1/53.61263
97340.118170.00100118.17P1080960 kDa heat shock protein, mitochondrial22835.7/61.01356

Only identified proteins are shown. Accession number: international database of the name and ID number of protein. Fold change: average density of the specific protein in males compared to females. Mowse score: measures reliability of the protein identification; greater than 100 ensures higher reliability that the protein identified is correct. Observed pI/Mr: isoelectric point and molecular weight of the protein. Ms/Ms: number of peptides sequenced after digestion. Total sequence coverage: percentage of the peptide sequenced.

Spot
number
Mean of normalized
volume of male
Mean of normalized
volume of female
Fold changes
(female/male)
Accession number
(Swiss-Prot)
Protein IDMowse
score
Observed pI/Mr
(KDr)
Number of peptides
by MS/MS
Total seq.
coverage (%)

7780.03170.12573.97P19971Thymidine phosphorylase 3265.2/55.0831
9470.40370.96772.40O14773Tripeptidyl-peptidase I 4275.7/47.6319
15260.04020.08552.13P07355Annexin A24227.6/38.6636
23420.01820.04432.44Q16781Ubiquitin-conjugating enzyme E2 N1345.7/15.7222
25360.05750.13122.28P01884Beta-2-microglobulin 1076.0/12.0234
49170.25271.01224.01CAA23759Unnamed protein product10047.0/13.6295
49470.06570.14402.19NP_004842Napsin A preproprotein16785.3/35.0322
88440.00280.051318.12Q02818Nucleobindin-12825.2/53.81129
91580.08930.18522.07 1JHW_AChain A, Ca2+-binding mimicry in the crystal structure of the Eu3+-bound mutant human macrophage capping protein cap G10634.9/26.3534
92070.01120.05104.57P07203Glutathione peroxidase3205.5/24.2454
95010.04470.09222.06P43686-2Proteasome 26S ATPase subunit 4 isoform 21925.0/62.7318
96290.07250.21783.00P07237Protein disulfide-isomerase9374.8/57.1834
96580.02450.10524.29P26038Moesin5396.1/67.9613

Only identified proteins are shown. Accession number: international database of the name and ID number of protein. Fold change: average density of the specific protein in males compared to females. Mowse score: measures reliability of the protein identification; greater than 100 ensures higher reliability that the protein identified is correct. Observed pI/Mr: isoelectric point and molecular weight of the protein. Ms/Ms: number of peptides sequenced after digestion. Total sequence coverage: percentage of the peptide sequenced.

4. Discussion

The current study indicates that in a population of HIV-infected smokers there are gender differences in pulmonary function and respiratory symptoms. Males have an increased prevalence of cough and phlegm production, as well as lower % of predicted FEV1 and a higher % of predicted RV. HRCT scanning demonstrated a trend to increased air trapping. Of note, the degree of diffusion impairment was similar between the two sexes as was the degree of emphysema on chest CT. The overall findings suggest among the HIV-infected population, male smokers may be more likely to develop early airways dysfunction than female smokers.

Studies examining gender differences among individuals with COPD in the general population suggest that women may be more susceptible to the effects of cigarette smoke. In a study by Silverman and colleagues [5] gender differences in severe early-onset COPD were studied by examining 84 early-onset COPD subjects and 348 of their first degree relatives. They found a similar level of airflow obstruction in male and female subjects; however, females had a tendency to smoke less. In first degree relatives, when analyzing current or exsmokers, female first degree relatives had a significantly lower FEV1/FVC ratio, significantly greater bronchodilator response, and more likely to have an FEV1% predicted less than 40%. It has been suggested that women may have a specific phenotype of COPD, that is, more airway disease predominant, whereas men tend to have more of an emphysematous phenotype. Based on a retrospective review of 1438 patients with a diagnosis of COPD, spirometric evidence of airflow obstruction, and CT scan data, a significantly greater proportion of women had airway disease [3]. Sex differences may exist on computed tomography as well, as it appears that men may have more emphysema on CT than women for the same degree of obstruction [17].

Our study is somewhat different from other studies that have examined established, advanced COPD; instead, we studied a group of at risk smokers finding that airway symptoms and loss of FEV1 appear to be more common in men. While airways disease seemed to be less affected in our population of women, diffusion impairment was prominent. Interestingly other studies on the non-HIV infected population have suggested that early in the presentation of COPD, women may have less airway disease, but greater diffusion impairment [18]. Furthermore, phlegm production has been seen to be more prominent in men with early COPD and respiratory symptoms better correlate with abnormal spirometry in men compared to women [19]. The different phenotypic expression of COPD at an early stage may in part explain why women are diagnosed at a later stage. Processes affecting gas exchange may be more clinically subtle and may not point to COPD as compared to airways disease. It should also be noted that the gender differences we have found may involve pathogenic factors unique to HIV and may not translate to the general population of smokers.

Our results differ from those of Gingo and colleagues who have recently reported lung function and respiratory symptoms among a cohort of HIV-infected subjects [7]. While both the diffusion impairment and respiratory symptoms were prominent in their population, the investigators did not report sex differences. Notably the populations are somewhat different as Gingo and colleagues included both smokers and never-smokers, while our analyses were confined smokers (either current or former). Furthermore, Gingo and coworkers grouped respiratory symptoms in their analyses, possible missing differences among types of symptoms (i.e., airway symptoms versus dyspnea) [7].

A limitation of our study was the disproportionate number of males compared to females, a reflection of the HIV-population in Central Ohio. Future studies, such as the ongoing multicenter Lung HIV study, are prospectively investigating lung function, and respiratory symptoms in over 4000 subjects [8]. Results of this investigation should provide additional insight into potential differences in respiratory outcomes among male and female smokers with HIV.

In addition to symptoms, PFTs, and radiographic difference, we performed alveolar macrophage proteomics in a subgroup of matched females and males to explore potential mechanisms underlying the phenotypic differences in this population. A number of proteins were significantly different between the two sexes. This hypothesis generating approach involves the investigation of the protein content of a biological system [20, 21]. Since biological phenotypes are largely determined by proteins, differential expression of certain proteins may have mechanistic implications with regard to the gender differences we have identified. These data are limited by the small number of subjects that were able to have bronchoscopy and alveolar macrophage proteomics. However, in this subset of patients, cathepsin D propreprotein and procathepsin H (both lysosomal proteins) are expressed at higher levels in the male group. It has been shown that Cathepsin D contributes to the multiple disease processes including breast cancer [22], Alzheimer disease [23], and HIV [24]. For example, Cathepsin D can modify the conformation of HIV-1 gp120 that in turn directly interacts with the CXCR4 coreceptor and thus enhances HIV infectivity by promoting the entry of HIV into cells [24]. Conceivably, Cathepsin D may contribute to the earlier manifestation of airway symptoms among the male HIV-infected smokers. Interestingly, cathepsin H has been shown to be upregulated in an IL-13 induced emphysema murine model [25]. Cathepsin H has also been shown to have a role in surfactant generation [26]. Another study showed that IFN gamma decreased the levels of surfactant protein B and it was thought to be through reduction in cathepsin H [27]. SP-B may be important in COPD susceptibility and frequency of exacerbations [28]. It is not clear what the cause or consequence of elevated procathepsin H levels in AM from HIV-infected men, but it is tempting to think it may play a role in the difference in symptoms between men and women. Cleary, these proteomic studies are “hypothesis generating” and follow-up studies are needed to further investigate these observations.

A recent study analyzed gender differences in the proteome of BAL cells in healthy smokers and subjects with COPD. They compared healthy nonsmokers, healthy smokers, and subjects with COPD, while we compared HIV-infected smokers. However, there are some similarities with both studies finding dysregulation of lysosomal proteins in females. In their cohort there was downregulation of cathepsin B in female subjects with COPD as compared with healthy smokers [29].

In conclusion, among a group of relatively young HIV-infected smokers there appear to be differences in the manifestation of respiratory abnormalities, as men seem to develop airway symptoms earlier than women, while both groups have prominent abnormalities in gas exchange. Alveolar macrophage proteomics demonstrate differences in protein expression between the two groups which may provide mechanistic insight. Future study into this phenomenon is warranted as this process may provide insight into COPD pathogenesis in the general population.

Abbreviations

COPD:Chronic obstructive pulmonary disease
ART:Antiretroviral
HRCT:High resolution computed tomography
AM:Alveolar macrophage
BAL:Bronchoalveolar lavage
FEV1:Forced expiratory volume in one second
RV:Residual volume
DLCO:Diffusing capacity for carbon monoxide
HIV:Human immunodeficiency virus.

Disclosure

The work was supported in part by the NIH and therefore in accordance with their public access policy is required to be placed in PubMed Central upon acceptance.

Conflict of Interests

All of the authors report no financial conflict of interests in relation to the completion of this research.

Acknowledgments

The authors would like to thank Janice Drake and Karen Martin for clinical study coordination and technical support. This work was supported by the following Grants from the NIH: HL083478 and HL090313 and NCRR CTSA award UL1RR025755.

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Copyright © 2014 Shiva D. Rahmanian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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