Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases

Mitochondria are essential organelles for cell metabolism, growth, and function. Mitochondria in lung cells have important roles in regulating surfactant production, mucociliary function, mucus secretion, senescence, immunologic defense, and regeneration. Disruption in mitochondrial physiology can be the central point in several pathophysiologic pathways of chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and asthma. In this review, we summarize how mitochondria morphology, dynamics, redox signaling, mitophagy, and interaction with the endoplasmic reticulum are involved in chronic lung diseases and highlight strategies focused on mitochondrial therapy (mito-therapy) that could be tested as a potential therapeutic target for lung diseases.

Overview of the Presentation and Updated Management of Sinusitis

Acute and chronic sinusitis are common primary care presentations. They are caused by mucosal inflammation, which inhibits mucociliary function of the nose and paranasal sinuses. Because it affects the mucous membranes that line both the nose and the sinuses, the complete medical word for sinusitis is "rhinosinusitis". Sinusitis is usually caused by a viral upper respiratory tract infection, with bacterial sinusitis occurring in about 2% of cases, yet in most cases overall antibiotics are being used and prescribed which is in most part are not needed, and cases often resolves without antibiotics need, most general practitioners rely on clinical findings to make the diagnosis. Watchful waiting and symptom treatment with nasal oxymetazoline, pseudoephedrine, and saline nasal irrigation are recommended. In this paper, we overview the presentation and management of sinusitis.

Antimicrobial Resistance in Common Respiratory Pathogens of Chronic Bronchiectasis Patients: A Literature Review

Non-cystic fibrosis bronchiectasis is a chronic disorder in which immune system dysregulation and impaired airway clearance cause mucus accumulation and consequent increased susceptibility to lung infections. The presence of pathogens in the lower respiratory tract causes a vicious circle resulting in impaired mucociliary function, bronchial inflammation, and progressive lung injury. In current guidelines, antibiotic therapy has a key role in bronchiectasis management to treat acute exacerbations and chronic infection and to eradicate bacterial colonization. Contrastingly, antimicrobial resistance, with the risk of multidrug-resistant pathogen development, causes nowadays great concern. The aim of this literature review was to assess the role of antibiotic therapy in bronchiectasis patient management and possible concerns regarding antimicrobial resistance based on current evidence. The authors of this review stress the need to expand research regarding bronchiectasis with the aim to assess measures to reduce the rate of antimicrobial resistance worldwide.

Bioengineered airway epithelial grafts with mucociliary function based on collagen IV- and laminin-containing extracellular matrix scaffolds

Current methods to replace damaged upper airway epithelium with exogenous cells are limited. Existing strategies use grafts that lack mucociliary function, leading to infection and the retention of secretions and keratin debris. Strategies that regenerate airway epithelium with mucociliary function are clearly desirable and would enable new treatments for complex airway disease.Here, we investigated the influence of the extracellular matrix (ECM) on airway epithelial cell adherence, proliferation and mucociliary function in the context of bioengineered mucosal grafts. In vitro, primary human bronchial epithelial cells (HBECs) adhered most readily to collagen IV. Biological, biomimetic and synthetic scaffolds were compared in terms of their ECM protein content and airway epithelial cell adherence.Collagen IV and laminin were preserved on the surface of decellularised dermis and epithelial cell attachment to decellularised dermis was greater than to the biomimetic or synthetic alternatives tested. Blocking epithelial integrin α2 led to decreased adherence to collagen IV and to decellularised dermis scaffolds. At air–liquid interface (ALI), bronchial epithelial cells cultured on decellularised dermis scaffolds formed a differentiated respiratory epithelium with mucociliary function. Using in vivo chick chorioallantoic membrane (CAM), rabbit airway and immunocompromised mouse models, we showed short-term preservation of the cell layer following transplantation.Our results demonstrate the feasibility of generating HBEC grafts on clinically applicable decellularised dermis scaffolds and identify matrix proteins and integrins important for this process. The long-term survivability of pre-differentiated epithelia and the relative merits of this approach against transplanting basal cells should be assessed further in pre-clinical airway transplantation models.

Mycoplasma hyopneumoniae surface-associated proteases cleave bradykinin, substance P, neurokinin A and neuropeptide Y

Mycoplasma hyopneumoniae is an economically-devastating and geographically-widespread pathogen that colonises ciliated epithelium, and destroys mucociliary function. M. hyopneumoniae devotes ~5% of its reduced genome to encode members of the P97 and P102 adhesin families that are critical for colonising epithelial cilia, but mechanisms to impair mucociliary clearance and manipulate host immune response to induce a chronic infectious state have remained elusive. Here we identified two surface exposed M. hyopneumoniae proteases, a putative Xaa-Pro aminopeptidase (MHJ_0659; PepP) and a putative oligoendopeptidase F (MHJ_0522; PepF), using immunofluorescence microscopy and two orthogonal proteomic methodologies. MHJ_0659 and MHJ_0522 were purified as polyhistidine fusion proteins and shown, using a novel MALDI-TOF MS assay, to degrade four pro-inflammatory peptides that regulate lung homeostasis; bradykinin (BK), substance P (SP), neurokinin A (NKA) and neuropeptide Y (NPY). These findings provide insight into the mechanisms used by M. hyopneumoniae to influence ciliary beat frequency, impair mucociliary clearance, and initiate a chronic infectious disease state in swine, features that are a hallmark of disease caused by this pathogen.

Spatial Intra- and Intercellular Alignment of Respiratory Cilia and its Relation to Function

Ciliary alignment is considered necessary to establish respiratory tract mucociliary clearance, and disorientation is often associated with primary ciliary dyskinesia. Therefore, there is an urgent need for a detailed analysis of ciliary orientation (CO). We used volume electron microscopy to examine CO relative to the tracheal long axis (TLA) by measuring the inter- and intracellular basal body orientation (BBO) and axonemal orientation (AO), which are considered to coincide, both equivalently indicating the effective stroke direction. Our results, however, reveal that only the mean BBO is aligned with the TLA, whereas the AO determines the effective stroke direction as well as the mucociliary transport direction. Furthermore, we show that even if the mean CO is conserved across cell boundaries, a considerable gradient in CO exists within individual cells, which we suspect to be crucial for the emergence of coordinated ciliary activity. Our findings provide new quantitative insight into CO and correlate this new structural information with mucociliary function.

Cigarette and ENDS preparations differentially regulate ion channels and mucociliary clearance in primary normal human bronchial 3D cultures

Cigarette smoking is known to disrupt the normal mucociliary function of the lungs, whereas the effect of electronic nicotine delivery systems (ENDS) is not completely understood. This study aimed to compare the effects of acute exposure of primary normal human bronchial epithelial (NHBE) 3D cultures at air-liquid interface to combustible cigarette and ENDS preparations on mucociliary function, including ion channel function, ciliary beat frequency (CBF), and airway surface liquid (ASL) height. Differentiated NHBE cultures were exposed to whole smoke-conditioned media (WS-CM) or total particulate matter (TPM) prepared from 3R4F reference cigarettes, whole aerosol-conditioned media (ACM) or e-TPM generated from a marketed ENDS product, or nicotine alone. We found that a dose of 7 μg/mL equi-nicotine units of cigarette TPM and WS-CM significantly decreased cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial sodium channel (ENaC) function, which regulates fluid homeostasis in the lung. Conversely, higher (56 µg/mL) equi-nicotine units of ENDS preparations or nicotine alone had no effect on CFTR and ENaC function. Despite a significant decrease in ion channel function, cigarette smoke preparations did not alter CBF and ASL. Similarly, ENDS preparations and nicotine alone had no effect on ASL and CBF. This study demonstrates that acute exposures of cigarette smoke preparations exert a notable inhibitory effect on CFTR and ENaC function compared with ENDS preparations. In summary, the functional assays described herein are potentially useful for tobacco product evaluations.

Eustachian tube functional assessment among patients with CSOM undergoing tympanoplasty surgery

<p class="abstract"><strong>Background:</strong> Pre-operative test of eustachian tube (ET) function is important for achieving a satisfactory result of tympanoplasty for CSOM patients. The saccharin test and methylene blue test seems to provide adequate information of the mucociliary function and patency of the ET. The aim was to study the ventilatory and mucociliary function of Eustachian tube in patients with chronic suppurative otitis media planned for tympanoplasty surgery and to assess the success rate of tympanoplasty in relation to the Eustachian tube function</p><p class="abstract"><strong>Methods:</strong> A prospective longitudinal study was conducted for a period of one year. Patients aged more than 15 years with features of chronic suppurative otitis media of either tubotympanic type or atticoantral type were included in the study. The total number of study subjects included in our study was 82 patients with CSOM. The ventilatory and the mucociliary functions of the auditory tube were assessed preoperatively using saccharin test and methylene blue test. All patients with CSOM underwent tympanoplasty surgery and the outcome of the surgery was assessed. </p><p class="abstract"><strong>Results:</strong> The overall success rate of tympanoplasty surgery was 76.8%. It was observed in our study that the success rate of tympanoplasty was higher among patients with normal eustachian tube function.</p><p class="abstract"><strong>Conclusions:</strong> Preoperative evaluation of eustachian tube function is mandatory for all the patients planned for tympanoplasty. Preoperative and intraoperative corrective measures should be taken in patients with partial and absent tubal function to improve the success rate of tympanoplasty surgeries.</p><p> </p>