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Cell and Tissue Research Mar 2017To fulfill the task of gas exchange, the lung possesses a huge inner surface and a tree-like system of conducting airways ventilating the gas exchange area. During lung... (Review)
Review
To fulfill the task of gas exchange, the lung possesses a huge inner surface and a tree-like system of conducting airways ventilating the gas exchange area. During lung development, the conducting airways are formed first, followed by the formation and enlargement of the gas exchange area. The latter (alveolarization) continues until young adulthood. During organogenesis, the left and right lungs have their own anlage, an outpouching of the foregut. Each lung bud starts a repetitive process of outgrowth and branching (branching morphogenesis) that forms all of the future airways mainly during the pseudoglandular stage. During the canalicular stage, the differentiation of the epithelia becomes visible and the bronchioalveolar duct junction is formed. The location of this junction stays constant throughout life. Towards the end of the canalicular stage, the first gas exchange may take place and survival of prematurely born babies becomes possible. Ninety percent of the gas exchange surface area will be formed by alveolarization, a process where existing airspaces are subdivided by the formation of new walls (septa). This process requires a double-layered capillary network at the basis of the newly forming septum. However, in parallel to alveolarization, the double-layered capillary network of the immature septa fuses to a single-layered network resulting in an optimized setup for gas exchange. Alveolarization still continues, because, at sites where new septa are lifting off preexisting mature septa, the required second capillary layer will be formed instantly by angiogenesis. The latter confirms a lifelong ability of alveolarization, which is important for any kind of lung regeneration.
Topics: Animals; Embryonic Development; Humans; Lung; Organogenesis; Pulmonary Alveoli
PubMed: 28144783
DOI: 10.1007/s00441-016-2545-0 -
Comprehensive Physiology Mar 2016Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to... (Review)
Review
Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints.
Topics: Adaptation, Physiological; Animals; Humans; Lung; Pulmonary Gas Exchange
PubMed: 27065169
DOI: 10.1002/cphy.c150028 -
BMC Pulmonary Medicine Oct 2018Pulmonary function tests (PFTs) are routinely performed in the upright position due to measurement devices and patient comfort. This systematic review investigated the...
BACKGROUND
Pulmonary function tests (PFTs) are routinely performed in the upright position due to measurement devices and patient comfort. This systematic review investigated the influence of body position on lung function in healthy persons and specific patient groups.
METHODS
A search to identify English-language papers published from 1/1998-12/2017 was conducted using MEDLINE and Google Scholar with key words: body position, lung function, lung mechanics, lung volume, position change, positioning, posture, pulmonary function testing, sitting, standing, supine, ventilation, and ventilatory change. Studies that were quasi-experimental, pre-post intervention; compared ≥2 positions, including sitting or standing; and assessed lung function in non-mechanically ventilated subjects aged ≥18 years were included. Primary outcome measures were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC, FEV1/FVC), vital capacity (VC), functional residual capacity (FRC), maximal expiratory pressure (PEmax), maximal inspiratory pressure (PImax), peak expiratory flow (PEF), total lung capacity (TLC), residual volume (RV), and diffusing capacity of the lungs for carbon monoxide (DLCO). Standing, sitting, supine, and right- and left-side lying positions were studied.
RESULTS
Forty-three studies met inclusion criteria. The study populations included healthy subjects (29 studies), lung disease (nine), heart disease (four), spinal cord injury (SCI, seven), neuromuscular diseases (three), and obesity (four). In most studies involving healthy subjects or patients with lung, heart, neuromuscular disease, or obesity, FEV1, FVC, FRC, PEmax, PImax, and/or PEF values were higher in more erect positions. For subjects with tetraplegic SCI, FVC and FEV1 were higher in supine vs. sitting. In healthy subjects, DLCO was higher in the supine vs. sitting, and in sitting vs. side-lying positions. In patients with chronic heart failure, the effect of position on DLCO varied.
CONCLUSIONS
Body position influences the results of PFTs, but the optimal position and magnitude of the benefit varies between study populations. PFTs are routinely performed in the sitting position. We recommend the supine position should be considered in addition to sitting for PFTs in patients with SCI and neuromuscular disease. When treating patients with heart, lung, SCI, neuromuscular disease, or obesity, one should take into consideration that pulmonary physiology and function are influenced by body position.
Topics: Humans; Lung; Posture; Respiratory Function Tests
PubMed: 30305051
DOI: 10.1186/s12890-018-0723-4 -
JAMA May 2023There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).
IMPORTANCE
There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).
OBJECTIVE
To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.
DESIGN, SETTING, AND PARTICIPANTS
The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.
INTERVENTIONS
Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.
MAIN OUTCOMES AND MEASURES
The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).
RESULTS
At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.
CONCLUSIONS AND RELEVANCE
Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.
TRIAL REGISTRATION
ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.
Topics: Aged; Humans; Male; Idiopathic Pulmonary Fibrosis; Lung; Quality of Life; Randomized Controlled Trials as Topic; Respiratory Physiological Phenomena; Treatment Outcome; Clinical Trials, Phase III as Topic; Multicenter Studies as Topic; Administration, Oral; Middle Aged; Female; Phosphodiesterase Inhibitors; Respiratory System Agents
PubMed: 37159034
DOI: 10.1001/jama.2023.5355 -
Physiology (Bethesda, Md.) Sep 2017Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function,... (Review)
Review
Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function, dysfunction, and failure. Here, we review methods of quantifying RV-PV interactions and experimental results from clinical trials as well as large- and small-animal models based on pressure-volume analysis. We conclude by outlining critical gaps in knowledge that should drive future studies.
Topics: Animals; Heart Ventricles; Humans; Lung; Pulmonary Veins
PubMed: 28814495
DOI: 10.1152/physiol.00040.2016 -
Magnetic Resonance in Medicine Jan 2022Lung stiffness alters with many diseases; therefore, several MR elastography (MRE) studies were performed earlier to investigate the stiffness of the right lung during...
PURPOSE
Lung stiffness alters with many diseases; therefore, several MR elastography (MRE) studies were performed earlier to investigate the stiffness of the right lung during breathhold at residual volume and total lung capacity. The aims of this study were 1) to estimate shear stiffness of the lungs using MRE under free breathing and demonstrate the measurements' repeatability and reproducibility, and 2) to compare lung stiffness under free breathing to breathhold and as a function of age and gender.
METHODS
Twenty-five healthy volunteers were scanned on a 1.5 Tesla MRI scanner. Spin-echo dual-density spiral and a spin-echo EPI MRE sequences were used to measure shear stiffness of the lungs during free breathing and breathhold at midpoint of tidal volume, respectively. Concordance correlation coefficient and Bland-Altman analyses were performed to determine the repeatability and reproducibility of the spin-echo dual-density spiral-derived shear stiffness. Repeated measures analyses of variances were used to investigate differences in shear stiffness between spin-echo dual-density spiral and spin-echo EPI, right and left lungs, males and females, and different age groups.
RESULTS
Free-breathing MRE sequence was highly repeatable and reproducible (concordance correlation coefficient > 0.86 for both lungs). Lung stiffness was significantly lower in breathhold than in free breathing (P < .001), which can be attributed to potential stress relaxation of lung parenchyma or breathhold inconsistencies. However, there was no significant difference between different age groups (P = .08). The left lung showed slightly higher stiffness values than the right lung (P = .14). There is no significant difference in lung stiffness between genders.
CONCLUSION
This study demonstrated the feasibility of free-breathing lung MRE with excellent repeatability and reproducibility. Stiffness changes with age and during the respiratory cycle. However, gender does not influence lungs stiffness.
Topics: Echo-Planar Imaging; Elasticity Imaging Techniques; Female; Humans; Lung; Magnetic Resonance Imaging; Male; Reproducibility of Results
PubMed: 34463400
DOI: 10.1002/mrm.28986 -
International Journal of Molecular... Aug 2020The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a... (Review)
Review
The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Humans; Lung; Lung Neoplasms; Models, Biological; Receptors, Notch; Signal Transduction
PubMed: 32784481
DOI: 10.3390/ijms21165691 -
Korean Journal of Radiology Oct 2021To describe the anatomic locations and imaging features of posterior lung herniation in unilateral pulmonary agenesis and aplasia, focusing on radiograph-CT/MRI...
OBJECTIVE
To describe the anatomic locations and imaging features of posterior lung herniation in unilateral pulmonary agenesis and aplasia, focusing on radiograph-CT/MRI correlation.
MATERIALS AND METHODS
A total of 10 patients (seven with pulmonary agenesis and three with pulmonary aplasia, male: female = 1:9, mean age 7.3 years, age range from 1 month to 20 years) were included. Chest radiographs (n = 9), CT (n = 9), and MRI (n = 1) were reviewed to assess the type of lung underdevelopment, presence of anterior and posterior lung herniation, bronchus origin, supplying artery, and draining vein of the herniated lung.
RESULTS
Pulmonary agenesis/aplasia more commonly affected the left lung (n = 7) than the right lung (n = 3). Anterior lung herniation was observed in nine of the 10 patients. Posterior lung herniation was observed in seven patients with left pulmonary agenesis/aplasia. Two patients showed posterior lung herniation crossing the midline but not beyond the aorta, and five patients showed the posteriorly herniated right lower lobe crossing the midline to extend into the left hemithorax farther beyond the descending thoracic aorta through the space between the esophagus and the aorta. This anatomical configuration resulted in a characteristic radiographic finding of a radiolucent area with a convex lateral border and a vertical medial border in the left lower lung zone, revealing a tongue-like projection on CT and MRI.
CONCLUSION
Posterior lung herniation occurs in unilateral left lung agenesis/aplasia. Approximately 70% of the cases of posterior lung herniation reveal a unique radiolucent tongue-like projection in the left lower lung zone on imaging studies, which is caused by the extension of the posteriorly herniated right lung farther beyond the descending aorta.
Topics: Abnormalities, Multiple; Child; Female; Humans; Infant; Lung; Lung Diseases; Male; Tomography, X-Ray Computed
PubMed: 34269531
DOI: 10.3348/kjr.2021.0155 -
Current Opinion in Pulmonary Medicine Sep 2016Pulmonary tumour thrombotic microangiopathy (PTTM) describes tumour cell microemboli with occlusive fibrointimal remodelling in small pulmonary arteries, veins and... (Review)
Review
PURPOSE OF REVIEW
Pulmonary tumour thrombotic microangiopathy (PTTM) describes tumour cell microemboli with occlusive fibrointimal remodelling in small pulmonary arteries, veins and lymphatics. Progressive vessel occlusion ultimately results in pulmonary hypertension, which is often severe and rapid in onset. PTTM is associated with carcinomas, notably gastric carcinoma, with vascular endothelial growth factor and platelet-derived growth factor (PDGF) signalling implicated in driving the intimal remodelling. PTTM is a rare cause of pulmonary hypertension, but given that up to a quarter of autopsy specimens from patients dying of carcinoma show evidence for PTTM, it is probably underdiagnosed.
RECENT FINDINGS
Until recently, prognosis in PTTM was universally abysmal from weeks to a few months. Diagnostic utilities include aspiration of tumour cells at wedged right heart catheterization, high-resolution computed tomography (HRCT) findings and computed tomography-positron emission tomography (CT-PET), although definitive diagnosis requires histological analysis. Reports of PTTM treated with a combination of targeted pulmonary vasodilator therapies, anticoagulation, specific chemotherapy and PDGF inhibition, for example using imatinib, suggest that these approaches can prolong survival.
SUMMARY
PTTM is increasingly recognized as an important cause of pulmonary hypertension, often in patients presenting with new-onset pulmonary hypertension and as yet undiagnosed malignancy. Prospects of survival are improving with targeted combination therapy, and early recognition and diagnosis are likely to be the key factors to improve outcome.
Topics: Humans; Lung; Lung Neoplasms; Neoplastic Cells, Circulating; Thrombotic Microangiopathies; Vascular Remodeling
PubMed: 27387102
DOI: 10.1097/MCP.0000000000000297 -
Journal of Cardiothoracic Surgery Mar 2022Giant lung bullae (GLB) are rare, and the only currently available management involves either an open surgical resection (thoracotomy) or the newer minimally invasive...
BACKGROUND
Giant lung bullae (GLB) are rare, and the only currently available management involves either an open surgical resection (thoracotomy) or the newer minimally invasive resection consisting of video-assisted thoracoscopic surgery (VATS). The aim of our study was to evaluate the possible influence of GLBs pulmonary attachment on patient's post-operative complications.
METHODS
A retrospective analysis included all consecutive patients with GLBs who underwent bullae's surgical resection from 7/2007 to 12/2018. GLBs patient's individual characteristics, including demographics, comorbidities, and clinical pre-operative, surgical intra-operative and post-operative data were evaluated.
RESULTS
20 patients with GLBs, 15 males and 5 females with average age of 48.9 years (range, 22-67 years) underwent 21 surgical procedures. The GLBs were located in the right lung in 12 patients, in the left lung in seven patients, and in both lungs in one patient. Fifteen patients (75%) were symptomatic on admission and underwent urgent surgery. Five asymptomatic patients (25%) were operated on electively. Thirteen from 21 surgical procedures (61.9%) were VATS bullectomy, while the other eight were thoracotomies (38.1%). Complications included pneumonia successfully treated with intravenous antibacterial therapy in two thoracotomy patients and in one VATS patient (three patients, 14.2%) and a prolonged air leak in two thoracotomy and four VATS patients (six patients, 28.5%). Out of 21 GLBs, eight had a wide attachment with lung parenchyma (wide-based bullae's) and 13 had a short attachment (short-based bullae's). Two re-operated patients, with prolonged air leak complicated with empyema, had a wide-based GLBs. The median hospital stay was nine days. All patients completed the 24-month follow-up.
CONCLUSIONS
Minimally invasive video-assisted thoracoscopic surgery as an open thoracotomy surgery is a safe and effective for giant lung bullae (GLB). Patients with wide-based GLBs were more likely to develop postoperative prolonged air leak that requiring re-operation.
Topics: Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Retrospective Studies; Thoracic Surgery, Video-Assisted; Thoracotomy
PubMed: 35292061
DOI: 10.1186/s13019-022-01780-3