BACKGROUND:Chronic Obstructive Pulmonary Disease (COPD) is a multifactorial disorder influenced by environmental exposures and genetic factors. The Hedgehog signaling pathway, particularly the PTCH1 receptor, plays a critical role in lung development, epithelial repair, and airway remodeling. However, its genetic contribution to COPD remains unclear. OBJECTIVE:To evaluate the association of PTCH1 polymorphic variants (rs56161606 and rs41313327) with COPD susceptibility and clinical phenotypes in a North Indian population. METHODOLOGY:A case-control study was conducted involving 500 COPD patients and 500 controls. Genotyping was performed on PTCH1 polymorphic variants (rs56161606 and rs41313327) using PCR-RFLP. Logistic regression was applied, adjusting for age, sex, and smoking. Genotype-phenotype associations were assessed using spirometric parameters, GOLD-COPD classification, and COPD symptoms. RESULTS:PTCH1 variants were not associated with overall COPD susceptibility. However, rs41313327 demonstrated an age-dependent effect, with the TT genotype increasing COPD risk in individuals aged ≥57 years (aOR = 1.8, p = 0.03). The rs56161606 variant was significantly associated with prolonged disease duration, increased mucus hypersecretion (aOR = 1.6, p = 0.04), exacerbation risk (aOR = 2.4, p = 0.02), and a genotype-dependent decline in the FEV1/FVC ratio (p < 0.05), suggesting its role in airflow obstruction. Furthermore, rs56161606 exhibited phenotype-specific associations with dyspnea and physical activity, highlighting its potential influence on the clinical heterogeneity of COPD. CONCLUSION:The PTCH1 rs56161606 polymorphism did not correlate with overall COPD susceptibility but appeared to be a possible genetic modulator of disease severity, affecting pulmonary function and phenotype-specific clinical symptoms. These results highlight the significance of Hedgehog signaling in airway remodeling and tissue repair mechanisms that contribute to the clinical heterogeneity of COPD.
OBJECTIVES:To evaluate recent advances and current challenges in inhaled aerosol dosimetry research, with a focus on understanding how particles affect human health through deposited doses, and to identify key research needs for improving exposure assessment and risk evaluation. METHODS:The findings were based on discussions and presentations from the Fourth International Aerosol Dosimetry Conference held in 2024 in Irvine, California. The conference used plenary sessions to promote cross-disciplinary communication and collaboration. Topics included computational models and simulations, in vitro and in vivo aerosol exposure systems, and variability in inhaled aerosol deposition. State-of-the-art research was presented, followed by open discussions to identify knowledge gaps and future priorities. RESULTS:Significant advances were reported in computational modeling, particularly in integrating different model types to better represent all major regions of the respiratory tract. Improvements in in vitro exposure systems enhanced particle delivery, dose measurement, and applicability to human health studies. Research also highlighted the importance of the upper airways as entry routes for inhaled medications. Dose variability emerged as a critical issue across aerosol dosimetry studies. New findings showed that inhaled ultrafine particles may acquire surface coatings after deposition and can penetrate tissues, including fetal tissues. Standardization and validation of in vitro approaches were identified as essential steps for reducing reliance on animal testing and improving human risk assessment. CONCLUSION:Internal aerosol dosimetry research continues to advance through improved models, exposure systems, and mechanistic understanding of deposited particle behavior. However, addressing dose variability, standardizing alternative testing methods, and improving data sharing remain essential for advancing risk assessment and supporting more accurate evaluations of inhaled particle effects on human health.
BACKGROUND:Increased ambient temperature alongside concomitant heatwaves and wildfire smoke imperil human health. We examined whether long-term episodic exposure to wildfire smoke induced greater respiratory injury/inflammation in male rats subchronically housed at elevated temperature or consuming unhealthy, cholesterol-rich diets. Respiratory effects of wildfire eucalyptus smoke exposure (WFES; ∼7mg/m3 particulate matter) were assessed 2h and 24h post-exposure in rats housed at 22 °C (room temperature; RT) consuming normal diet (ND) and exposed to filtered air (FA) or WFES for 1h. METHODS:To determine effects of ongoing exposure, 4-5-week-old rats were subchronically housed at RT or high temperature (HT; 30-31°C) and fed ND or high-cholesterol (2%) diet (HCD). Rats were episodically exposed to FA or WFES 1h/d, 1d/wk, for 12-13wk. 48h after final exposure, bronchoalveolar lavage fluid (BALF) lung injury and inflammation, gene expression, and lung/nasal pathology were assessed. RESULTS:Acute WFES exposure increased BALF markers of lung injury and neutrophilic inflammation. Subchronic HT resulted in >30% lower weight gain and decreased body fat relative to RT; effects were greater in episodically WFES-exposed rats. Whole body plethysmography revealed HT-induced changes in breathing parameters; WFES exacerbated these effects. Small effects were observed on BALF markers of lung injury/inflammation, consistent with minimal pathological findings in lung and nasal cavity. All three stressors, individually and in combination, inhibited gene expression of proteins involved in glucocorticoid-mediated regulation of neuroendocrine stress response and peripheral homeostatic physiology. CONCLUSION:These findings suggest functional impairment at HT, exacerbated by WFES, linked to dysregulation of stress without affecting structural integrity of respiratory tract.
BACKGROUND:Ambient air pollution is associated with reduced lung function, but whether sex modifies the association with threshold-based exposures remains unclear. This cross-sectional study examined sex-specific associations between threshold-based exposures to fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and lung function. METHODS:Data from 21,339 adults aged 45-85 years in the Canadian Longitudinal Study on Aging were analyzed. Annual average air pollutant concentrations representing multi-year exposure estimates (2012-2015) were assigned to participants based on their residential postal codes. Decision tree regression was used to derive exposure cut points and classify participants into low, intermediate, and high exposure thresholds for each pollutant with respect to lung function (FEV1, FVC, and FEV1/FVC ratio). Survey-weighted multivariable linear regression models were used to estimate sex-specific associations with percent-predicted lung function, including interaction terms between sex and exposure thresholds. RESULTS:Significant sex interactions were observed for PM2.5 and NO2 with percent-predicted FEV1 and FVC, and for O3 with percent-predicted FVC and the FEV1/FVC ratio. Among males, high vs. low PM2.5 exposure was associated with lower FEV1 (-3.11%; 95% CI: -4.47, -1.74) and FVC (-2.72%; 95% CI: -3.76, -1.69). Among females, a significant but smaller FVC reduction was observed (-1.53%; 95% CI: -2.59, -0.47) but not for FEV1. High vs. low NO2 exposure was associated with greater reductions in FEV1 among males (-5.00%; 95% CI: -7.16, -2.84) than among females (-1.99%; 95% CI: -2.79, -1.19), and significantly reduced FVC among males(-3.58%; 95% CI: -5.15, -2.00) but not among females (-1.64%; 95% CI: -3.39, 0.11). High vs. low O3 exposure was associated with reduced FVC in both sexes, with a stronger association among males (-3.34%; 95% CI: -4.37, -2.31) than among females (-2.60%; 95% CI: -3.56, -1.65). CONCLUSIONS:Sex significantly modified the inverse associations between ambient air pollution exposure thresholds and lung function, with greater reductions observed in males. These associations occurred at exposure thresholds at or below current regulatory standards, underscoring the need for continuous reassessment of air quality guidelines to better protect respiratory health.
OBJECTIVE:Heat-not-burn tobacco products (IQOS) have emerged as potentially reduced-risk alternatives to combustible cigarettes (CSs), yet their inhalation toxicity profile remains incompletely characterized. MATERIALS AND METHODS:This study evaluated the comparative respiratory and systemic effects of IQOS aerosol vs. CS smoke through whole-body inhalation exposure in an experimental rat model. Twenty-one male Wistar albino rats (8-10 weeks, 250-300 g) were randomly assigned to three groups (n = 7): control (ambient air), CS exposure (10 mg nicotine/day, ∼6 cigarettes/session), and IQOS exposure (equivalent nicotine dose, ∼8 HeatSticks/session). A custom-designed whole-body inhalation exposure system, developed in collaboration with Istanbul Technical University, delivered standardized aerosols following Health Canada Intense puffing parameters (55 mL puff volume, 27.5 mL/s flow rate, 2-s puff duration, 30-s inter-puff interval) during daily 1.5-h sessions over 21 consecutive days. Peripheral blood samples were collected on Days 7, 14, and 21 for assessment of plasma inflammatory markers (IL-1β, IL-6, TNF-α, and hs-CRP), oxidative stress parameters (total oxidant status [TOS], total antioxidant status, oxidative stress index), and DNA damage in isolated mononuclear leukocytes using the alkaline comet assay. Plasma cotinine was quantified as the primary biomarker of systemic nicotine absorption. Terminal lung tissue analysis on Day 21 evaluated local respiratory oxidative stress, inflammatory cytokine concentrations, and tissue cotinine deposition. . RESULTS:Plasma TOS increased progressively in both exposure groups (CS: 9.2 ± 1.82 to 14.71 ± 1.65 µmol H2O2 Eq/L; IQOS: 6.81 ± 1.25 to 11.49 ± 1.30 µmol H2O2 Eq/L), with CS demonstrating significantly higher oxidative burden. DNA damage in circulating cells escalated markedly (CS: 21.74 ± 2.51% to 47.76 ± 3.67% tail DNA; IQOS: 16.22 ± 1.87% to 33.44 ± 2.41% tail DNA). Lung tissue analysis revealed significant 'elevation of inflammatory markers and oxidative stress parameters' in both exposure groups. While IQOS inhalation induced less severe toxicity than CS smoke, it produced significant respiratory and systemic adverse effects including oxidative stress, inflammatory responses, and DNA damage. DISCUSSION AND CONCLUSION:These findings challenge claims of substantially reduced harm for heat-not-burn products and support continued regulatory oversight of inhaled tobacco delivery systems.
