Pathogenesis Of Chronic Lung Disease Research Articles

A comprehensive review of Mycoplasma pneumoniae infection in chronic lung diseases: recent advances in understanding asthma, COPD, and bronchiectasis.

This review summarizes the research progress over the past 30 years on the relationship between Mycoplasma pneumoniae infection and chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. Mycoplasma pneumoniae is a common cause of community-acquired pneumonia, particularly in children and young adults. Key findings from recent studies indicate that M. pneumoniae infection is associated with a higher risk of asthma exacerbations and may contribute to the development of bronchiectasis in susceptible individuals. Additionally, emerging evidence suggests that M. pneumoniae-induced immune dysregulation plays a crucial role in the pathogenesis of chronic lung diseases. This review aims to summarize the current understanding of the potential links between M. pneumoniae pneumonia and various chronic respiratory conditions, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. We discuss the epidemiological data, pathogenic mechanisms, clinical manifestations, and long-term consequences of M. pneumoniae-related respiratory illnesses. Additionally, we highlight the challenges in diagnosis and treatment, as well as future research directions in this field.

Development of novel technology for the visualization and quantitation of microvascular progenitor-driven adaptive angiogenesis during chronic lung disease

Introduction: Adaptive angiogenesis can drive repair or underlie the pathogenesis of tissue remodeling. Pulmonary vascular dysfunction is a major manifestation of chronic lung disease (CLD) but the role of angiogenesis in CLD is not well defined. Microvascular capillaries are the vessels most affected by pruning and remodeling in the lung resulting in reduced capillary length and density. Our lab has previously demonstrated that microvascular progenitors (ABCG2+ MVPCs) drive adaptive angiogenesis or loss of tissue structure downstream of the Wnt or mTOR signaling pathways. Therefore, we hypothesize that visualization of the pulmonary microvasculature and MVPC-driven adaptive angiogenesis in three-dimensions is essential to define the role of MVPC-driven adaptive angiogenesis during repair or the pathogenesis of CLD. Methods: To evaluate the contribution of Wnt activated MVPCs to angiogenesis in three-dimensions during injury repair, we crossed ABCG2-CreERT2 mice to a BOE strain (flΔex3) with stabilized β-catenin expression and a fluorescent membrane eGFP reporter strain to facilitate lineage tracing. The development and resolution of fibrosis were induced in vivo via aspiration of bleomycin sulfate (0.05U). Mice were retro-orbitally perfused with fluorescently conjugated tomato lectin. Lung tissue was inflated with agarose and up to 500μm thickness precision cut lung slices (PCLS) were mounted for imaging. PCLS were imaged on the Zeiss LSM900 and Z-stacks were obtained. Imaris software (Oxford Instruments) was used for three-dimensional reconstruction and FIJI and Wimasis Image Analysis (Onimagin Technologies) were utilized to segment vessels, quantitate vessel density, volume, diameter, and length. Results: Following perfusion, vascular staining of both the lung and kidney was observed, suggesting successful systemic perfusion and labeling. The pulmonary microvasculature was visualized to a diameter of 1-3μm in high fidelity. We observed a significant reduction in vessel density in mice treated with bleomycin compared to mice treated with a vehicle control. In our three-dimensional reconstructions we observed increased density of ABCG2+ MVPC-derived de novo angiogenic structures in areas of fibrosis. Conclusion: De novo angiogenesis driven by ABCG2+ MVPCs likely plays a role in tissue repair following bleomycin induced lung injury. In addition, we have developed a simple and reliable perfusion technique allowing for the visualization and quantitation of the pulmonary microvasculature in three-dimensions. This tool will allow the quantitation of microvessel remodeling underlying pathogenesis and repair in multiple lung injury models. Thus, this methodology will further support the study and understanding of angiogenesis during CLD and repair following injury. This approach may be utilized in various organ systems to visualize microvasculature structure and its role in disease. NIA RAG073317 NHLBI 1R35HL161238. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Influence of adipocytokines on the bronchopulmonary system in abdominal obesity

Pathogenesis of chronic lung diseases is assumed to involve systemic inflammation factors, as well as hormone-like substances adipokines produced by adipose tissue, which is an independent endocrine organ. Adipokines cause systemic inflammation under the influence of hypoxemia due to obesity and associated respiratory disorders such as obstructive sleep apnea syndrome, chronic obstructive pulmonary disease, hypoventilation syndrome, etc. However, the influence of specific adipocytes on the development and course of bronchopulmonary diseases remains unclear.Purpose of this review was to evaluate the contribution of some adipocytokines to the development of bronchopulmonary conditions against abdominal obesity. We collected data on adiponectin, adipsin, lipocalin-2, interleukin 6, insulin, glucagon, leptin, monocyte-chemoattractant protein type 1, tumor necrosis factor-α, amylin, glucose-dependent insulinotropic polypeptide, ghrelin, and pancreatic polypeptide in patients with abdominal obesity and bronchopulmonary disorders.Conclusion. The presented data confirm that hormone-like substances produced by adipose tissue make a significant contribution to the severity of respiratory disorders.

Lung inflammation and interstitial fibrosis by targeted alveolar epithelial type I cell death.

The pathogenesis of chronic lung diseases is multifaceted with a major role of recurrent micro-injuries of the epithelium. While several reports clearly indicated a prominent role for surfactant-producing alveolar epithelial type 2 (AT2) cells, the contribution of gas exchange-permissive alveolar epithelial type 1 (AT1) cells has not been addressed yet. Here, we investigated whether repeated injury of AT1 cells leads to inflammation and interstitial fibrosis. We chose an inducible model of AT1 cell depletion following local diphtheria toxin (DT) administration using an iDTR flox/flox (idTRfl/fl) X Aquaporin 5CRE (Aqp5CRE) transgenic mouse strain. We investigated repeated doses and intervals of DT to induce cell death of AT1 cells causing inflammation and interstitial fibrosis. We found that repeated DT administrations at 1ng in iDTRfl/fl X Aqp5CRE mice cause AT1 cell death leading to inflammation, increased tissue repair markers and interstitial pulmonary fibrosis. Together, we demonstrate that depletion of AT1 cells using repeated injury represents a novel approach to investigate chronic lung inflammatory diseases and to identify new therapeutic targets.

Microcomputed tomography visualization and quantitation of the pulmonary arterial microvascular tree in mouse models of chronic lung disease.

Pulmonary vascular dysfunctionis characterized by remodeling and loss of microvessels in the lung and is a major manifestation of chronic lung diseases (CLD). In murine models of CLD, the small arterioles and capillaries are the first and most prevalent vessels that are affected by pruning and remodeling. Thus, visualization of the pulmonary arterial vasculature in three dimensions is essential to define pruning and remodeling both temporally and spatially and its role in the pathogenesis of CLD, aging, and tissue repair. To this end, we have developed a novel method to visualize and quantitate the murine pulmonary arterial circulation using microcomputed tomography(µCT) imaging. Using this perfusion technique, we can quantitate microvessels to approximately 6 µM in diameter. We hypothesize that bleomycin-induced injury would have a significant impact on the arterial vascular structure. As proof of principle, we demonstrated that as a result of bleomycin-induced injury at peak fibrosis, significant alterations in arterial vessel structure were visible in the three-dimensional models as well as quantification. Thus, we have successfully developed a perfusion methodology and complementary analysis techniques, which allows for the reconstruction, visualization, and quantitation of the mouse pulmonary arterial microvasculature in three-dimensions. This tool will further support the examination and understanding of angiogenesis during the development of CLD as well as repair following injury.

Elevated Levels of Interleukin-1β and Interleukin-10 Are Associated With Faster Lung Function Decline in People With Well-Treated Human Immunodeficiency Virus.

People with human immunodeficiency virus (PWH) have an increased risk of chronic lung diseases and chronic inflammation. We aimed to investigate if inflammatory markers and monocyte activation are associated with faster lung function decline in PWH. We included 655 PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Eligible participants were aged ≥25 years and had 2 spirometries separated by >2 years. Inflammatory markers (interleukin [IL]-1β, IL-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) were measured at baseline by Luminex, and soluble CD14 and soluble CD163 by enzyme-linked immunosorbent assay. Using linear mixed models, we investigated whether elevated cytokine levels were associated with faster lung function decline. The majority of PWH were males (85.2%) with undetectable viral replication (95.3%). We found a faster decline in forced expiratory volume in 1 second (FEV1) in PWH with elevated IL-1β and IL-10, with an additional decline of 10.3 mL/year (95% confidence interval [CI], 2.1-18.6; P = .014) and 10.0 mL/year (95% CI, 1.8-18.2; P = .017), respectively. We found no interaction between smoking and IL-1β or IL-10 on FEV1 decline. Elevated IL-1β and IL-10 were independently associated with faster lung function decline in PWH, suggesting that dysregulated systemic inflammation may play a role in the pathogenesis of chronic lung diseases.

High‐resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome‐wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked to fibroblast repair processes using phenotypic screens. Our study provides high‐resolution multi‐omic maps of HLFs across COPD stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic lung diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

Gut microbiota modulates lung fibrosis severity following acute lung injury in mice

Independent studies demonstrate the significance of gut microbiota on the pathogenesis of chronic lung diseases; yet little is known regarding the role of the gut microbiota in lung fibrosis progression. Here we show, using the bleomycin murine model to quantify lung fibrosis in C57BL/6 J mice housed in germ-free, animal biosafety level 1 (ABSL-1), or animal biosafety level 2 (ABSL-2) environments, that germ-free mice are protected from lung fibrosis, while ABSL-1 and ABSL-2 mice develop mild and severe lung fibrosis, respectively. Metagenomic analysis reveals no notable distinctions between ABSL-1 and ABSL-2 lung microbiota, whereas greater microbial diversity, with increased Bifidobacterium and Lactobacilli, is present in ABSL-1 compared to ABSL-2 gut microbiota. Flow cytometric analysis reveals enhanced IL-6/STAT3/IL-17A signaling in pulmonary CD4 + T cells of ABSL-2 mice. Fecal transplantation of ABSL-2 stool into germ-free mice recapitulated more severe fibrosis than transplantation of ABSL-1 stool. Lactobacilli supernatant reduces collagen 1 A production in IL-17A- and TGFβ1-stimulated human lung fibroblasts. These findings support a functional role of the gut microbiota in augmenting lung fibrosis severity.

Mucins MUC5AC and MUC5B Are Variably Packaged in the Same and in Separate Secretory Granules.

Rationale: MUC5AC (mucin 5AC, oligomeric gel-forming) and MUC5B (mucin 5B, oligomeric gel-forming) are the predominant secreted polymeric mucins in mammalian airways. They contribute differently to the pathogenesis of various muco-obstructive and interstitial lung diseases, and their genes are separately regulated, but whether they are packaged together or in separate secretory granules is not known. Objectives: To determine the packaging of MUC5AC and MUC5B within individual secretory granules in mouse and human airways under varying conditions of inflammation and along the proximal-distal axis. Methods: Lung tissue was obtained from mice stimulated to upregulate mucin production by the cytokines IL-1β and IL-13 or by porcine pancreatic elastase. Human lung tissue was obtained from donated normal lungs, biopsy samples of transplanted lungs, and explanted lungs from subjects with chronic obstructive pulmonary disease. MUC5AC and MUC5B were labeled with antibodies from different animal species or, in mice only, by transgenic chimeric mucin-fluorescent proteins and imaged using widefield deconvolution or Airyscan fluorescence microscopy. Measurements and Main Results: In both mouse and human airways, most secretory granules contained both mucins interdigitating within the granules. Smaller numbers of granules contained MUC5B alone, and even fewer contained MUC5AC alone. Conclusions: MUC5AC and MUC5B are variably stored both in the same and in separate secretory granules of both mice and humans. The high fraction of granules containing both mucins under a variety of conditions makes it unlikely that their secretion can be differentially controlled as a therapeutic strategy. This work also advances knowledge of the packaging of mucins within secretory granules to understand mechanisms of epithelial stress in the pathogenesis of chronic lung diseases.

Altered pharmacology and toxicology during ageing: implications for lung disease.

Drug use in elderly people is high compared to younger people. Simultaneously, elderly are at greater risk when exposed to environmental substances. It is puzzling therefore, that ageing, as a variable in pharmacological and toxicological processes is not investigated in more depth. Moreover, recent data suggest that molecular manifestations of the ageing process also hallmark the pathogenesis of chronic lung diseases, which may impact pharmacology and toxicology. In particular, absorption, distribution, metabolism and excretion (ADME) processes of drugs and toxins alter because of ageing. Polypharmacy, which is quite usual with increasing age, increases the risk of drug-drug interactions. Individual differences in combination of drugs use in conjunction with individual variations in drug metabolizing enzymes can influence lung function. Exploring exposure throughout life (i.e. during ageing) to potential triggers, including polypharmacy, may avoid lung disease or unexplained cases of lung damage. Understanding of the ageing process further unravels critical features of chronic lung disease and helps to define new protective targets and therapies. Optimizing resilience can be key in pharmacology and toxicology and helps in maintaining healthy lungs for a longer period.

An epigenome-wide study of DNA methylation profiles and lung function among American Indians in the Strong Heart Study

BackgroundEpigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45–74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989–1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993–1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.ResultsAmong 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein–protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.ConclusionWe found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.

The Human Mycobiome in Chronic Respiratory Diseases: Current Situation and Future Perspectives.

Microbes play an important role in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma. While the role of bacterial pathogens has been extensively studied, the contribution of fungal species to the pathogenesis of chronic lung diseases is much less understood. The recent introduction of next-generation sequencing techniques has revealed the existence of complex microbial lung communities in healthy individuals and patients with chronic respiratory disorders, with fungi being an important part of these communities’ structure (mycobiome). There is growing evidence that the components of the lung mycobiome influence the clinical course of chronic respiratory diseases, not only by direct pathogenesis but also by interacting with bacterial species and with the host’s physiology. In this article, we review the current knowledge on the role of fungi in chronic respiratory diseases, which was obtained by conventional culture and next-generation sequencing, highlighting the limitations of both techniques and exploring future research areas.

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease.

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

Prevalence and antimicrobial resistance profiles of respiratory microbial flora in African children with HIV-associated chronic lung disease

BackgroundHIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi.MethodsNasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score < − 1 without reversibility post-bronchodilation with salbutamol), at enrolment as part of a randomised, placebo-controlled trial of azithromycin (BREATHE trial - NCT02426112), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression.ResultsA total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13–18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1–3.9]), younger age (SP: aOR 3.2 [1.8–5.8]), viral load suppression (SP: aOR 0.6 [0.4–1.0], SA: 0.5 [0.3–0.9]), stunting (SP: aOR 1.6 [1.1–2.6]) and male sex (SA: aOR 1.7 [1.0–2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4–7.3], SA: 2.1 [1.1–4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1–0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2–4.4]).ConclusionsCLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.

Mitochondrial Dysfunction in Chronic Respiratory Diseases: Implications for the Pathogenesis and Potential Therapeutics.

Mitochondria are indispensable for energy metabolism and cell signaling. Mitochondrial homeostasis is sustained with stabilization of mitochondrial membrane potential, balance of mitochondrial calcium, integrity of mitochondrial DNA, and timely clearance of damaged mitochondria via mitophagy. Mitochondrial dysfunction is featured by increased generation of mitochondrial reactive oxygen species, reduced mitochondrial membrane potential, mitochondrial calcium imbalance, mitochondrial DNA damage, and abnormal mitophagy. Accumulating evidence indicates that mitochondrial dysregulation causes oxidative stress, inflammasome activation, apoptosis, senescence, and metabolic reprogramming. All these cellular processes participate in the pathogenesis and progression of chronic respiratory diseases, including chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. In this review, we provide a comprehensive and updated overview of the impact of mitochondrial dysfunction on cellular processes involved in the development of these respiratory diseases. This not only implicates mechanisms of mitochondrial dysfunction for the pathogenesis of chronic lung diseases but also provides potential therapeutic approaches for these diseases by targeting dysfunctional mitochondria.

The role of MIF in chronic lung diseases: looking beyond inflammation.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been associated with many diseases. Most studies found in literature describe MIF as a proinflammatory cytokine involved in chronic inflammatory conditions, but evidence from last years suggests that many of its key effects are not directly related to inflammation. In fact, MIF is constitutively expressed in most human tissues and in some cases in high levels, which does not reflect the pattern of expression of a classic proinflammatory cytokine. Moreover, MIF is highly expressed during embryonic development and decreases during adulthood, which point toward a more likely role as growth factor. Accordingly, MIF knockout mice develop age-related spontaneous emphysema, suggesting that MIF presence (e.g., in younger individuals and wild-type animals) is part of a healthy lung. In view of this new line of evidence, we aimed to review data on the role of MIF in the pathogenesis of chronic lung diseases.

Potential Role of Cellular Senescence in Asthma

Cellular senescence is a complicated process featured by irreversible cell cycle arrest and senescence-associated secreted phenotype (SASP), resulting in accumulation of senescent cells, and low-grade inflammation. Cellular senescence not only occurs during the natural aging of normal cells, but also can be accelerated by various pathological factors. Cumulative studies have shown the role of cellular senescence in the pathogenesis of chronic lung diseases including chronic obstructive pulmonary diseases (COPD) and idiopathic pulmonary fibrosis (IPF) by promoting airway inflammation and airway remodeling. Recently, great interest has been raised in the involvement of cellular senescence in asthma. Limited but valuable data has indicated accelerating cellular senescence in asthma. This review will compile current findings regarding the underlying relationship between cellular senescence and asthma, mainly through discussing the potential mechanisms of cellular senescence in asthma, the impact of senescent cells on the pathobiology of asthma, and the efficiency and feasibility of using anti-aging therapies in asthmatic patients.

Clinical-morphological study of lung diseases in basic treatment with the use of antioxidants of different origin and without

Annotation. The purpose of the work is to analyze contemporary views on the morphological changes of lung tissue in inflammatory disease in the clinical and experimental conditions and results of correction by using the antioxidants. The analysis is based in a review if foreign articles for 2014-2019, using the scientometric databases PubMed, Web of Science and Google Scholar. According to the latest data from WHO and WORLD HEALTH RANKINGS 5-year mortality rate of such disease as COPD typically ranges from 40% to 70%, depending on disease severity, while the 2-year mortality rate for people with severe COPD is about 50%. We know that almost 90% of COPD deaths occur in low- and middle-income countries such as Ukraine. Thereby mortality rate from lung tissue diseases in Ukraine is 11.11%. These diseases often accompanied by inflammation and oxidative stress. The last can cause mitochondrial dysfunction, dynamic changes and mitophagy impairment, which leads to increase the number of superoxide anions, hydrogen peroxide etc., inflammatory responses and cellular senescence. They all play important roles in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and bronchopulmonary dysplasia. Many studies in vitro approved the role of antioxidants in the decreasing of the degree of morphological changes: inflammatory cells infiltration and alveolar edema, permeability and inflammation. In vivo disease development is mainly related to the many conditions, but closely to its severity and possible of combination with other diseases. Thereby treatment of such diseases by using e.g. leaves extract of different herbs can be prescribe to ameliorate the level of reactive oxygen species and decrease the possible cell injure made by anti-inflammatory medicines.

Mitochondrial Dysfunction as a Pathogenic Mediator of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

The mechanisms underlying the pathogenesis of chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis, remain incompletely understood. Mitochondria are vital cellular organelles crucial for energy generation, the maintenance of cellular metabolism, calcium homeostasis, intracellular signaling, and the regulation of cell death programs. Emerging evidence suggests that mitochondrial dysfunction plays a cardinal role in the initiation and progression of many human diseases, including chronic lung diseases. Upregulation of the autophagy program, a cellular adaptive mechanism for protein and organelle turnover, can occur in response to injury and may have a cell type-specific impact on the progression of disease. The selective autophagy subtype specific for mitochondria (mitophagy), regulated by PINK1 (phosphatase and tensin homolog-induced putative kinase 1), is a cellular response to accumulation of depolarized or injured mitochondria. Autophagy and mitophagy may be associated with either cellular protection or propagation of injury in a cell type-specific manner, and they may also be associated with modulation of cell death pathways. Genetic studies in mouse models have revealed opposing roles for PINK1 and/or mitophagy in the propagation of emphysema and fibrosis, whereas human studies have shown altered regulation of PINK1 in both idiopathic pulmonary fibrosis and COPD. We have also recently identified a role for mitophagy in regulating the cellular necroptosis program, with implications in COPD pathogenesis. Damage-associated molecular patterns released from injured mitochondria and/or necrotic cells may promote proinflammatory and profibrotic responses. In this review, we explore current experimental evidence for mitochondrial dysfunction as a key determinant in the pathogenesis of chronic lung diseases.

Intraperitoneal Glucose Tolerance Test, Measurement of Lung Function, and Fixation of the Lung to Study the Impact of Obesity and Impaired Metabolism on Pulmonary Outcomes.

Obesity and respiratory disorders are major health problems. Obesity is becoming an emerging epidemic with an expected number of over 1 billion obese individuals worldwide by 2030, thus representing a growing socioeconomic burden. Simultaneously, obesity-related comorbidities, including diabetes as well as heart and chronic lung diseases, are continuously on the rise. Although obesity has been associated with increased risk for asthma exacerbations, worsening of respiratory symptoms, and poor control, the functional role of obesity and perturbed metabolism in the pathogenesis of chronic lung disease is often underestimated, and underlying molecular mechanisms remain elusive. This article aims to present methods to assess the effect of obesity on metabolism, as well as lung structure and function. Here, we describe three techniques for mice studies: (1) assessment of intraperitoneal glucose tolerance (ipGTT) to analyze the effect of obesity on glucose metabolism; (2) measurement of airway resistance (Res) and respiratory system compliance (Cdyn) to analyze the effect of obesity on lung function; and (3) preparation and fixation of the lung for subsequent quantitative histological assessment. Obesity-related lung diseases are probably multifactorial, stemming from systemic inflammatory and metabolic dysregulation that potentially adversely influence lung function and the response to therapy. Therefore, a standardized methodology to study molecular mechanisms and the effect of novel treatments is essential.