Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases (CVPD). Although cigarette smoking has been in constant decline since the 195...

Nicotine and the renin-angiotensin system

There is considerable evidence that matrix metalloproteinases (MMPs) are up- and/or downregulated in chronic obstructive pulmonary disease (COPD), particularly in emphysema, in which they probably participate in proteolytic attack on the alveolar wall matrix. Recent data suggest that MMPs also have major roles in driving inflammation or shutting it down, as well as modifying the release of fibrogenic growth factors, processes that are important in the genesis of the various lesions of COPD. In cigarette smoke-induced animal models of emphysema, MMP-12 appears to play a consistent and important role, whereas the data for other MMPs are difficult to interpret. In human lungs, evidence for a role for MMPs is more tenuous and there are numerous contradictions in the literature. Little is known about the effects of MMPs in small airway remodelling, smoke-induced pulmonary hypertension and chronic bronchitis, but MMP-12 participates in experimental small airway modelling. To date, the accumulated data suggest that selective inhibition of MMP-12 might be a viable therapy for emphysema and small airway remodelling, but subtle differences in the functions of MMP-12 in animals and humans mandate caution with this approach. Whether inhibition of other MMPs might be useful is unclear.

https://erj.ersjournals.com/content/erj/39/1/197.full.pdf

Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD.

COPD in China: The Burden and Importance of Proper Management

Acrolein is a respiratory irritant that can be generated during cooking and is in environmental tobacco smoke. More plentiful in cigarette smoke than polycyclic aromatic hydrocarbons (PAH), acrolein can adduct tumor suppressor p53 (TP53) DNA and may contribute to TP53-mutations in lung cancer. Acrolein is also generated endogenously at sites of injury, and excessive breath levels (sufficient to activate metalloproteinases and increase mucin transcripts) have been detected in asthma and chronic obstructive pulmonary disease (COPD). Because of its reactivity with respiratory-lining fluid or cellular macromolecules, acrolein alters gene regulation, inflammation, mucociliary transport, and alveolar-capillary barrier integrity. In laboratory animals, acute exposures have lead to acute lung injury and pulmonary edema similar to that produced by smoke inhalation whereas lower concentrations have produced bronchial hyperreactivity, excessive mucus production, and alveolar enlargement. Susceptibility to acrolein exposure is associated with differential regulation of cell surface receptor, transcription factor, and ubiquitin-proteasome genes. Consequent to its pathophysiological impact, acrolein contributes to the morbidly and mortality associated with acute lung injury and COPD, and possibly asthma and lung cancer.

Acrolein – a pulmonary hazard

Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance.

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: possible involvement of angiotensin-converting enzyme-2.

Background
Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-β1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH.

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Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality. It is influenced by both environmental and genetic factors. Aquaporin5 plays a critical role in the maintenance of normal lung water homeostasis. We investigated whether polymorphisms in the gene aquaporin5 had any bearing on individual susceptibility to the development of COPD. Methods: 332 COPD patients and 373 unrelated, age-matched healthy people were recruited for the study. All participants were Chinese Han people. We designed denaturing high performance liquid chromatography (DHPLC) to detect SNP in exons1, 2, 3 of AQP5 and DNA sequencing to confirm it. The allele +2254A>G (rs3736309) in intron3 and +3088A>G (Thr-Thr, rs41308104) in exon4 from NCBI dbSNP were genotyped by PCR-based restriction fragment length polymorphism. Results: We found no SNPs in exons1–4 of the AQP5 gene in our study population. However, the genotype frequency of +2254A>G SNP in intron3 was significantly different in cases and controls. The frequencies of AA AG GG in cases were 45.2%, 40.7%, and 14.1%, while in controls they were 34.5%, 51.6%, and 13.9% (c2 = 9.899, P = 0.007), respectively. Higher OR for COPD was seen for persons with +2254AA genotype against +2254AG genotype (OR = 2.73; 95%CI = 1.88–3.97). Carriers of the variant allele +2254G had a lower risk of COPD than homozygous wild type carriers (OR = 0.44; 95%CI = 0.307–0.631). Conclusion: The +2254A to G variant in intron 3 of AQP5 was associated with a decreased risk of COPD in a Chinese population.

Su-Xia Han

Papers

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: possible involvement of angiotensin-converting enzyme-2.

Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

Polymorphisms of aquaporin5 gene in chronic obstructive pulmonary disease in a Chinese population.

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog.