Monica P. Goldklang

Rationale: There is an increased incidence of alpha-1 antitrypsin deficiency carrier state in patients with chronic obstructive pulmonary disease, but the clinical relevance of a single pathogenic SERPINA1 allele needs investigation, with a limited understanding of clinical course in these patients. Methods: A single-center cohort of 309 consecutive patients with chronic obstructive pulmonary disease and SERPINA1 genotype was assembled between 2011 and 2018. Frequent exacerbators were defined as patients with 2 or more exacerbations per year. Results: 277 patients with the normal MM genotype were compared to 32 patients with an abnormal SERPINA1 genotype (20 MS and 12 MZ patients). There was no difference with regard to severity of chronic obstructive pulmonary disease determined by pulmonary function testing and Global Initiative for Chronic Obstructive Lung Disease stage between the groups. However, 35 of 277 MM patients (12.6%) were frequent exacerbators, compared to 8 of 20 patients with MS (40%) and 6 of 12 patients with MZ (50%), p<0.001. MM patients had 0.79±1.33 exacerbations per year compared to 1.37±1.13 in MS and 2.31±3.30 in MZ patients (p< 0.001). Conclusions: MS and MZ patients are phenotypically different than patients with MM with more frequent exacerbations of chronic obstructive pulmonary disease despite similar disease stage and degree of obstruction based on spirometry. These results emphasize the importance of genetic testing in patients with chronic obstructive pulmonary disease as a method to determine disease phenotype as well as the potential for abnormal SERPINA1 alleles to independently cause manifestations of disease progression.

Expression of the Receptor for Advanced Glycation Endproducts (RAGE) initiates pro-inflammatory pathways resulting in lung destruction. We hypothesized that RAGE directed imaging demonstrates increased lung uptake in smoke-exposure. After exposure to room air or to cigarette smoke for 4-weeks or 16-weeks, rabbits were injected with 99mTc-anti-RAGE F(ab’)2 and underwent Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging. Lung radiotracer uptake was calculated as percent injected dose (%ID). Lungs were dissected for gamma well counting and histological analysis. 99mTc-anti-RAGE F(ab’)2 SPECT/CT imaging demonstrated increased lung expression of RAGE with smoke exposure compared to room air control at 4-weeks: Room air right (R) 0.75 ± 0.38%ID, left (L) 0.62 ± 0.32%ID vs. Smoke exposed R 0.17 ± 0.03, L 0.17 ± 0.02%ID (p = 0.02 and 0.028, respectively). By 16-weeks of smoke exposure, the uptake decreased to 0.19 ± 0.05%ID R and 0.17 ± 0.05%ID L, significantly lower than 4-week imaging (p = 0.0076 and 0.0129 respectively). Staining for RAGE confirmed SPECT results, with the RAGE ligand HMGB1 upregulated in the macrophages of 4-week smoke-exposed rabbits. RAGE-directed imaging identified pulmonary RAGE expression acutely in vivo in an animal model of emphysema early after smoke exposure, with diminution over time. These studies document the extent and time course of RAGE expression under smoke exposure conditions and could be utilized for disease monitoring and examining response to future RAGE-targeted therapies.

Asthma is a chronic inflammatory disease mediated by allergen-specific CD4 T cells that promote lung inflammation through recruitment of cellular effectors into the lung. A subset of lung T cells can persist as tissue-resident memory T cells (TRMs) following infection and allergen induction, although the generation and role of TRM in asthma persistence and pathogenesis remain unclear. In this study, we used a mouse model of chronic exposure to intranasal house dust mite (HDM) extract to dissect how lung TRMs are generated and function in the persistence and pathogenesis of allergic airway disease. We demonstrate that both CD4⁺ and CD8⁺ T cells infiltrate into the lung tissue during acute HDM exposure; however, only CD4⁺ TRMs, and not CD8⁺ TRMs, persist long term following cessation of HDM administration. Lung CD4⁺ TRMs are localized around airways and are rapidly reactivated upon allergen re-exposure accompanied by the rapid induction of airway hyperresponsiveness independent of circulating T cells. Lung CD4⁺ TRM activation to HDM challenge is also accompanied by increased recruitment and activation of dendritic cells in the lungs. Our results indicate that lung CD4⁺ TRMs can perpetuate allergen-specific sensitization and direct early inflammatory signals that promote rapid lung pathology, suggesting that targeting lung CD4⁺ TRMs could have therapeutic benefit in alleviating recurrent asthma episodes.

AIM: To demonstrate a direct inhibitory effect of cigarette smoke exposure on paraoxonase 1 activity in a murine in vivo model. METHODS: At 8 weeks old, we randomized 10 C57/bl6 mice to an environment consisting of either filtered air or cigarette smoke for 6 months. Smoke exposure (7 hours per day, 5 days per week) was standardized using a model TE-10 smoking machine and adjusted to maintain constant sidestream and mainstream smoke. After 6 months of exposure, we assessed differences in lung air space, cholesterol, lipid, and lipoprotein profiles, as well as paraoxonase activity in mice exposed to cigarette smoke extract compared to unexposed control mice. RESULTS: Cigarette smoke exposure by the protocol used was sufficient to result in pathologic changes in lung architecture consistent with emphysema. Specifically, we observed that mice exposed to cigarette smoke had a significantly higher mean linear chord length compared to animals that were exposed to filtered air (p<0.02). Despite this exposure, no differences in total HDL-cholesterol levels or HDL-cholesterol sub-fractions (i.e. HDL2 and HDL3 fractions) were noted between smoke-exposed and unexposed animals (p=1.00, 0.6, and 0.4, respectively). Notably, mean HDL-cholesterol levels were identical between groups (92.8 vs 92.8 mg/dL, p=1.0). Paraoxonase activity, however, was markedly reduced in mice exposed to cigarette smoke compared to those who were not exposed (102, SD=9.6 vs 144, SD=4.1 units of activity, respectively, p=0.002). CONCLUSION: In this murine model, tobacco smoke exposure directly inhibits paraoxonase activity independently of HDL-cholesterol levels rather than indirectly via reduction in HDL-cholesterol levels.