Local pulmonary opioid network in patients with lung cancer: a putative modulator of respiratory function
Introduction
Recently, there has been growing interest in the local opioid regulation of the tracheobronchial mucociliary clearance [31, 38] and the smooth muscle broncho-constrictive response of the lung [3, 40]. Inhalation of β-endorphin (END) modulates the mucociliary clearance in dogs in a naloxone-reversible manner [38]. Opioid peptides also inhibit bronchial smooth muscle contractions induced by parasympathetic nerve stimulation; in turn, local naloxone antagonizes this inhibition suggesting an opioid receptor specific mechanism [15, 31]. Some clinical trials have indicated that patients might benefit from inhalation of nebulized opioids, but other clinical trials have not [18]. However, particularly terminally ill patients, such as those with lung cancer or end stage lung disease, seem to have significant relief from their dyspnea after treatment with nebulized opioids [8, 11, 13]. More recently, Mahler et al. demonstrated that endogenous opioids al-levate dyspnea during treadmill exercise in patients with chronic obstructive pulmonary disease [21].
Opioid peptides, their precursors and their receptors are located within the central nervous system. However, similar to other non-neuronal tissues, such as the gut, spleen, and skin [25, 27, 37], lung or lung cancer cell lines also contain some components of the opioid system. There is evidence for END in cell lines from human lung cancer [22, 32] and for opioid receptor binding sites in both human lung [5, 9] and lung carcinoma cell lines [22]. However, it is unknown if these components of the opioid system associate with functionally important anatomical structures of the respiratory system, such as submucosal bronchial glands, pulmonary neuroendocrine cells (PNECs), and the nerve fibers ofthe bronchial epithelium.
Posttranslational processing of proopiomelano-cortin (POMC) into the functionally active peptide END requires key enzymes such as carboxypeptidase E (CPE) and prohormone convertase 1 (PC1) and 2 (PC2) [4, 20, 27]. In contrast with the extensively studied, classical posttranslational processing of POMC in the pituitary gland [35], little is known about opioid peptide localization and processing within the human lung.
Because of the increasing interest in the opioid system of the lung, we systematically examined different areas of lung tissue from lung cancer patients for the expression of the precursor POMC; its processing enzymes PC1, PC2, and CPE; the POMC-derived active peptide END; and END’s corresponding opioid receptor (µ-opioid receptor, MOR). To illustrate local opioid effects, particularly in a terminally ill patient with lung cancer, we examined pulmonary function parameters after the inhalation of nebulized morphine. From these experiments, we hoped to provide a comprehensive neuroanatomical basis for a local opioid network regulating respiratory functions in the human lung.
Section snippets
Patients and preparation of human lung tissue
The study followed the International Guidelines of Declaration of Helsinki (World Medical Association: http://www.wma.net) and was approved by the Ethics Committee of the Nicolaus Copernicus University in Toruń, Poland. Human lung tissue samples were obtained from 16 lung cancer patients undergoing lobec-tomy or pneumectomy at the Department of Thoracic Surgery and Lung Disease of the Oncology Center in Bydgoszcz, Poland (Tab. 1). All patients were informed of the purpose of the study and gave
Anatomical and histological identification of END-IR cells in different areas of human lung tissue
Light microscope pictures with END immunoreactiv-ity showed END-IR cells within the anatomical and histological structure of human lung tissue. END im-munoreactivity was observed in sparse solitary cells within the bronchial epithelium (Fig. 1A), in alveolar macrophage-like cells accumulating within the alveolar lumen (Fig. 1B), and in cancerous cells infiltrating the lung tissue (Fig. 1C). There was no significant im-munoreactivity without the primary antibody or with an antibody against END
Discussion
Using a systematic approach, we were able to demonstrate within the lung tissue of lung cancer patients an endogenous opioid network that contained the essential components required for END synthesis and processing and contained the opioid receptors for END. Specifically, we showed the following: 1) identification of END-IR cells within different anatomical and histological structures of the human lung; 2) colocal-ization of the opioid precursor POMC with END, PC1, PC2 and CPE within alveolar
Acknowledgments
We are gratefulto Mrs. Ute Oedekoven’s for technicalassistance, Dr. Jan Sir for his contribution in microscopy, and Ms. Marzena Sykutera for her help in tissue preparation. We gratefully acknowledge the gift of antibodies and recombinant antigens from Drs. NG Seidah, Quebec, Canada; DF Steiner, University of Chicago, IL; and N Birch, University of Auckland, New Zealand (anti-PCI, anti-PC2, recombinant PC1 and PC2); Drs. Y Peng Loh and L Fricker, Albert Einstein College, NY [anti-CPE and
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These authors contributed equally to this work.