Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation.

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Squamous Cell Lung Carcinoma Presenting With Refractory Status Epilepticus: A Case Report of Paraneoplastic Limbic Encephalitis.

Lung cancer-associated paraneoplastic syndromes affecting the central nervous system present significant diagnostic and treatment challenges. In this case, the patient presented with personality change, cognitive impairment, complex partial seizures, ataxia, dyspraxia, and dysphasia. Shortly after admission, the patient suffered refractory generalized tonic-clonic seizures and a decreased level of consciousness and required intubation, ventilation, and admission to the ICU. He was subsequently diagnosed with paraneoplastic limbic encephalitis based on recognized criteria, including a compatible clinical picture, elevated protein content in his cerebrospinal fluid with negative cytology, a positive positron emission tomography-computed tomography scan showing a right upper lobe tumor, and the exclusion of other neuro-oncological complications. Histopathology confirmed the tissue diagnosis as squamous cell cancer. Initial immunotherapy with steroids and intravenous immunoglobulin and subsequent lobectomy and adjuvant chemotherapy were partially successful, leading to partial resolution of his cognitive impairment. This report highlights the diagnostic and therapeutic challenges of lung-related paraneoplastic syndromes. In addition, it illustrates the poor outcomes for patients and identifies squamous cell cancer as an extremely rare cause of paraneoplastic limbic encephalitis.