ABSTRACT
Pulmonary emphysema, a major component of chronic obstructive pulmonary diseases, is a highly prevalent progressive tissue-destructive disease, with no effective treatments. The interplay between inflammation, matrix proteolysis, oxidative stress and apoptosis might account for the irreversible progression of the disease. Recent investigations have underlined the importance of the lung vasculature in the pathobiology of chronic obstructive pulmonary diseases offering new therapeutic strategies. This review will focus on the pulmonary microvessels as a target in the treatment of pulmonary emphysema.
Subject(s)
Lung/blood supply , Pulmonary Emphysema , Animals , Apoptosis/drug effects , Capillaries/drug effects , Capillaries/immunology , Capillaries/pathology , Humans , Lung/immunology , Lung/pathology , Oxidative Stress/drug effects , Pulmonary Emphysema/immunology , Pulmonary Emphysema/pathology , Pulmonary Emphysema/therapy , Respiratory System Agents/therapeutic useABSTRACT
Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure. It includes a variety of pulmonary hypertensive diseases with different etiologies but similar clinical presentation. PAH is a disease of the small pulmonary arteries, characterized by progressive obliteration of the pulmonary vascular bed. Vasoconstriction, remodeling of the pulmonary vessel wall and thrombosis contribute to an increased pulmonary vascular resistance. Major advances in our understanding of the mechanism of disease development have been achieved over the past decade. Several of these new insights have led to the development and clinical application of novel treatments that includes new classes of drugs such as prostanoids, endothelin receptor antagonists and type 5 phosphodiesterase inhibitors.
Subject(s)
Hypertension, Pulmonary , Humans , Hypertension, Pulmonary/classification , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/therapyABSTRACT
The gastrointestinal peptides glucagon-like peptide-1(7-36)amide (GLP-1) and amylin are currently being tested in clinical trials for the treatment of diabetes mellitus due to their effects in lowering blood glucose. Receptors for these polypeptides also exist in the lung and since polypeptides are known to modulate airway and pulmonary vascular tone, we investigated whether GLP-1 and amylin act similarly in the lung. We compared their effects with the well-known actions of calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP). Both GLP-1 and amylin induced a dose-dependent and time-reversible endothelial-dependent relaxation of preconstricted pulmonary artery rings. Amylin was approximately as strong as VIP and CGRP, GLP-1 however, was 2.3-fold less potent. GLP-1 as well as amylin also reduced the vascular tone in the isolated, perfused and ventilated rat lung. In contrast to their action on the pulmonary vasculature, neither GLP-1 nor amylin showed any effect on the tone of isolated preconstricted trachea rings. In conclusion, GLP-1 and amylin represent two additional peptides which may modulate pulmonary vascular tone.
Subject(s)
Amyloid/pharmacology , Peptide Fragments/pharmacology , Pulmonary Circulation/drug effects , Vasodilation/drug effects , Acetylcholine/pharmacology , Animals , Anti-Ulcer Agents/pharmacology , Calcitonin Gene-Related Peptide/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Gastrointestinal Hormones/pharmacology , Glucagon , Glucagon-Like Peptide 1 , Glucagon-Like Peptides , In Vitro Techniques , Islet Amyloid Polypeptide , Male , NG-Nitroarginine Methyl Ester/pharmacology , Neurotransmitter Agents/pharmacology , Norepinephrine/pharmacology , Perfusion , Pulmonary Artery/drug effects , Pulmonary Ventilation , Rats , Rats, Sprague-Dawley , Trachea , Vasoactive Intestinal Peptide/pharmacology , Vasoconstrictor Agents/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
The recent discoveries of the familial primary pulmonary hypertension gene and somatic mutations in key cell growth and cell death regulatory genes in primary pulmonary hypertension have added a new dimension to severe pulmonary hypertension research. These findings have already impacted on how the disease is viewed, and ultimately, how severe pulmonary hypertension is diagnosed and treated. However, this new information raises several fundamental questions related to the role of bone morphogenetic protein receptor signalling in the control of lung vascular cell function. Furthermore, additional genes and gene products may also be involved in the pathogenesis of the disease. The way severe pulmonary hypertension is viewed and studied is on the verge of shifting from a vasoconstrictive to a cell growth paradigm.
Subject(s)
Hypertension, Pulmonary/genetics , Bone Morphogenetic Protein Receptors, Type II , DNA Mutational Analysis , Endothelium, Vascular/physiopathology , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Protein Serine-Threonine Kinases/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/genetics , Signal Transduction/physiologyABSTRACT
HOX genes belong to the large family of homeodomain genes that function as transcription factors. Animal studies indicate that they play an essential role in lung development. We investigated the expression pattern of HOX genes in human lung tissue by using microarray and degenerate reverse transcriptase-polymerase chain reaction survey techniques. HOX genes predominantly from the 3' end of clusters A and B were expressed in normal human adult lung and among them HOXA5 was the most abundant, followed by HOXB2 and HOXB6. In fetal (12 weeks old) and diseased lung specimens (emphysema, primary pulmonary hypertension) additional HOX genes from clusters C and D were expressed. Using in situ hybridization, transcripts for HOXA5 were predominantly found in alveolar septal and epithelial cells, both in normal and diseased lungs. A 2.5-fold increase in HOXA5 mRNA expression was demonstrated by quantitative reverse transcriptase-polymerase chain reaction in primary pulmonary hypertension lung specimens when compared to normal lung tissue. In conclusion, we demonstrate that HOX genes are selectively expressed in the human lung. Differences in the pattern of HOX gene expression exist among fetal, adult, and diseased lung specimens. The altered pattern of HOX gene expression may contribute to the development of pulmonary diseases.
Subject(s)
Genes, Homeobox , Hypertension, Pulmonary/genetics , Lung/metabolism , Pulmonary Emphysema/genetics , Adult , Animals , Gene Expression Profiling , Homeodomain Proteins/biosynthesis , Homeodomain Proteins/genetics , Humans , Hypertension, Pulmonary/metabolism , Lung/embryology , Mice , Multigene Family , Oligonucleotide Array Sequence Analysis , Phosphoproteins/biosynthesis , Phosphoproteins/genetics , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Pulmonary Emphysema/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transcriptional ActivationABSTRACT
Primary pulmonary hypertension (PPH) is a frequently fatal disease whose pathobiology is poorly understood. Monoclonal endothelial cell growth is present within plexiform lesions of patients with PPH but not secondary PH because of congenital heart malformations. We hypothesized that endothelial cells within PPH plexiform lesions harbor mutations permissive for clonal cell growth. We found that endothelial cells in PPH plexiform lesions demonstrated microsatellite instability within the human MutS Homolog 2 gene (10 of 20 lesions) and displayed microsatellite site mutations and reduced protein expression of transforming growth factor-beta receptor type II (6 of 19 lesions) and Bax (4 of 19 lesions). These results suggest that, in PPH, proliferated endothelial cells have genetic alterations associated with microsatellite instability and concomitant perturbation of growth and apoptosis gene expression akin to neoplasia. The full text of this article is available at http://www.circresaha.org.
