Lung Tissue Destruction Research Articles

Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling.

BackgroundDuring the pathological destruction of lung tissue, neutrophil elastase (NE) degrades elastin, one of the major constituents of lung parenchyma. However there are no non-invasive methods to quantify NE degradation of elastin. We selected specific elastin fragments generated by NE for antibody generation and developed an ELISA assay (EL-NE) for the quantification of NE-degraded elastin.MethodsMonoclonal antibodies were developed against 10 NE-specific cleavage sites on elastin. One EL-NE assay was tested for analyte stability, linearity and intra- and inter-assay variation. The NE specificity was demonstrated using elastin cleaved in vitro with matrix metalloproteinases (MMPs), cathepsin G (CatG), NE and intact elastin. Clinical relevance was assessed by measuring levels of NE-generated elastin fragments in serum of patients diagnosed with idiopathic pulmonary fibrosis (IPF, n = 10) or lung cancer (n = 40).ResultsAnalyte recovery of EL-NE for human serum was between 85% and 104%, the analyte was stable for four freeze/thaw cycles and after 24 h storage at 4°C. EL-NE was specific for NE-degraded elastin. Levels of NE-generated elastin fragments for elastin incubated in the presence of NE were 900% to 4700% higher than those seen with CatG or MMP incubation or in intact elastin. Serum levels of NE-generated elastin fragments were significantly increased in patients with IPF (137%, p = 0.002) and in patients with lung cancer (510%, p < 0.001) compared with age- and sex-matched controls.ConclusionsThe EL-NE assay was specific for NE-degraded elastin. The EL-NE assay was able to specifically quantify NE-degraded elastin in serum. Serum levels of NE-degraded elastin might be used to detect excessive lung tissue degradation in lung cancer and IPF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-015-0048-5) contains supplementary material, which is available to authorized users.

Metabolic pathways of Pseudomonas aeruginosa involved in competition with respiratory bacterial pathogens.

Background: Chronic airway infection by Pseudomonas aeruginosa considerably contributes to lung tissue destruction and impairment of pulmonary function in cystic-fibrosis (CF) patients. Complex interplays between P. aeruginosa and other co-colonizing pathogens including Staphylococcus aureus, Burkholderia sp., and Klebsiella pneumoniae may be crucial for pathogenesis and disease progression.Methods: We generated a library of PA14 transposon insertion mutants to identify P. aeruginosa genes required for exploitative and direct competitions with S. aureus, Burkholderia cenocepacia, and K. pneumoniae.Results: Whereas wild-type PA14 inhibited S. aureus growth, two transposon insertions located in pqsC and carB, resulted in reduced growth inhibition. PqsC is involved in the synthesis of 4-hydroxy-2-alkylquinolines (HAQs), a family of molecules having antibacterial properties, while carB is a key gene in pyrimidine biosynthesis. The carB mutant was also unable to grow in the presence of B. cepacia and K. pneumoniae but not Escherichia coli and S. epidermidis. We further identified a transposon insertion in purF, encoding a key enzyme of purine metabolism. This mutant displayed a severe growth deficiency in the presence of Gram-negative but not of Gram-positive bacteria. We identified a beneficial interaction in a bioA transposon mutant, unable to grow on rich medium. This growth defect could be restored either by addition of biotin or by co-culturing the mutant in the presence of K. pneumoniae or E. coli.Conclusion: Complex interactions take place between the various bacterial species colonizing CF-lungs. This work identified both detrimental and beneficial interactions occurring between P. aeruginosa and three other respiratory pathogens involving several major metabolic pathways. Manipulating these pathways could be used to interfere with bacterial interactions and influence the colonization by respiratory pathogens.

The effect of IL-17A deficiency on infection and inflammation is strain dependent in acute murine pneumonia

Background: Bacterial pneumonia is worldwide a leading cause of mortality. Acute and chronic inflammations leading to destruction of lung tissue, impaired pulmonary gas exchange, and lung edema are characteristic hallmarks of severe pneumonia. IL-17A has a function in the host defense against a variety of bacterial and fungal pathogens. It was the aim of this study to examine the role of IL-17A during acute murine pneumonia.

The importance of CFTR expression for neutrophil function in patients with Cystic Fibrosis

Background Cystic fibrosis (CF) is a genetic disease characterised by chronic bacterial infection of the lung and destruction of lung tissue eventually leading to respiratory failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Current treatment focuses on managing the symptoms of CF including antibiotic therapy against respiratory infections and vitamin and enzyme supplements to treat pancreatic insufficiency. However, a new drug known as ivacaftor has been approved recently that treats the underlying defect and corrects the defective CFTR in carriers of the G551D mutation. Neutrophils in CF fail to eradicate pathogens causing lung infections. Reports suggesting dysregulated neutrophil activity in CF illustrated altered gene expression and increased release of proteases from primary granules. However, it remains unknown whether neutrophil dysfunction is due to chronic inflammation or the CFTR defect. Our hypothesis is that impaired neutrophil activity in CF is directly caused by a lack of CFTR protein and function. Therefore, the aim of this study was to examine CFTR expression in neutrophils by optimising the methods for optimal CFTR protein detection, by comparing the levels of expression of mature CFTR protein in healthy control and CF neutrophils to epithelial cells and by examining the function of the CFTR channel in neutrophils.

Invited Commentary

Miyahara and colleagues [1Miyahara S. Nakai H. Izawa N. et al.Influences of chronic obstructive pulmonary disease on outcomes of total arch replacement.Ann Thorac Surg. 2015; 99: 72-79Scopus (11) Google Scholar] have provided an interesting analysis on the influence of chronic obstructive pulmonary disease (COPD) on the outcome of total arch replacement. The association between aortic wall degeneration and destruction of lung tissue is under current debate. COPD as well as aortic disease are important morbidities of an aging population. The prevalence of lung disease in patients with aortic disease is high, reaching up to 47% of patients with aortic arch pathologies and to even higher rates of 55% in patients with abdominal aortic aneurysms [2LeMaire S.A. Price M.D. Parenti J.L. et al.Early outcome after aortic arch replacement by using the Y-graft technique.Ann Thorac Surg. 2011; 91: 700-707Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 3Fowkes F.G. Anandan C.L. Lee A.J. et al.Reduced lung function in patients with abdominal aortic aneurysm is associated with activation of inflammation and hemostasis, not smoking or cardiovascular disease.J Vasc Surg. 2006; 43: 474-480Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. For this reason, careful preoperative assessment, especially spirometry, is usually recommended but carries a potential risk for patients with thoracic aortic disease due to changes of intrathoracic pressure. To avoid potential harm, patients are not assessed by spirometry preoperatively, and the presence or severity of COPD is overlooked or remains underdiagnosed. The data of Miyahara and colleagues [1Miyahara S. Nakai H. Izawa N. et al.Influences of chronic obstructive pulmonary disease on outcomes of total arch replacement.Ann Thorac Surg. 2015; 99: 72-79Scopus (11) Google Scholar] once again underline the importance of COPD as a risk factor for in-hospital death as well for postoperative pulmonary complications. Especially patients undergoing aortic arch replacement necessitating deep hypothermic circulatory arrest should be evaluated very carefully for preoperative lung disease. Ischemia-reperfusion can be the initiating factor for pulmonary dysfunction during and after extracorporeal circulation and can possibly induce devastating damage to already diseased lung tissue. Experimental data reveal an increase of inflammation factors interleukin-8 and interleukin-6, as well as activation of nuclear factor-κB, and might explain the mechanism of deep hypothermic circulatory arrest–induced pulmonary injury [4Zheng J.H. Gao B.T. Jiang Z.M. Yu X.Q. Xu Z.W. Evaluation of early macrophage activation and NF-kappaB activity in pulmonary injury caused by deep hypothermia circulatory arrest: an experimental study.Pediatr Cardiol. 2010; 31: 215-221Crossref PubMed Scopus (12) Google Scholar]. In summary, their report reflects daily clinical routine: the vast majority of patients with mild to moderate COPD do well, even after extended aneurysm repair. Those patients presenting with severe COPD and the definitive need deep hypothermic circulatory arrest have to be assessed very carefully. Influences of Chronic Obstructive Pulmonary Disease on Outcomes of Total Arch ReplacementThe Annals of Thoracic SurgeryVol. 99Issue 1PreviewAlthough an association between chronic obstructive pulmonary disease (COPD) and adverse surgical outcomes has been proposed, the impact of COPD severity on postoperative outcomes remains unclear. Our objective was to analyze the prognostic implication of COPD severity on outcomes after total aortic arch replacement. Full-Text PDF

Alpha-1 Antitrypsin Deficiency-Associated Chronic Obstructive Pulmonary Disease: A Family Perspective

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that can lead to the early onset of chronic obstructive pulmonary disease (COPD), a disorder that comprises elements of chronic bronchitis and emphysema. AATD is characterized by reduced levels of the AAT protease inhibitor, leading to unrestricted protease activity in the lung, which promotes destruction of lung tissue. In severe cases, patients with AATD have an increased mortality risk and, potentially, a poor quality of life due to more frequent COPD exacerbations and/or limitations on daily activity. However, the burden of AATD on members of the patient's immediate family who may serve as caregivers has not been described. Because the age range at which most patients are diagnosed with AATD may affect the economic status of an individual and/or of a family, it is likely that a diagnosis of AATD may have negative effects that extend beyond those on the diagnosed person to include immediate family members. Here, we review the literature to investigate the impact of the caregiver role of family members in disease states that affect an age group similar to AATD. Furthermore, we provide a case study showing the effect of AATD on immediate family members.

Efficiency of using rituximab in a patient with generalized granulomatosis with polyangiitis: A case report

Systemic vasculitides (SVs) are characterized by inflammation of the blood vessels wall; the spectrum of their clinical manifestations depends on the type, extent, and location of affected vessels and the activity of systemic inflammation. The etiology of most primary SVs is unknown. Antineutrophil cytoplasmic antibodies (ANCAs) are implicated in its pathogenesis. The presence of ANCAa in patients' serum and the correlation of their level with the severity of clinical manifestations served as a basis for identifying a subgroup of systemic necrotizing vasculitides associated with ANCA synthesis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and Churg – Strauss syndrome. GPA is characterized by systemic granulomatous necrotizing vasculitis involving the small vessels of the upper respiratory tract, lung, and kidney. The paper describes a case of difficult diagnosis and successful rituximab (RTM) treatment of generalized GPA in a 45-year-old female patients. The disease occurred with local damage to the upper respiratory tract, granulomatous inflammation of the pulmonary vessels to form multiple infiltrates with lung tissue destruction elements and necrotizing glomerulonephritis. Despite intensive immunosuppressive treatment, there was a rapid GPA progression with the further development of respiratory failure, which had been induced by stenotic laryngitis subglottica leading to tracheostoma. Damage to the organ of vision could lead to severe complications, including amaurosis. RMT was shown to be effective in treating generalized GPA with a poor prognosis.

The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, best characterized by the formation of proliferative nodules that express smooth muscle and melanocytic antigens within the lung parenchyma, leading to progressive destruction of lung tissue and function. The pathological basis of LAM is associated with Tuberous Sclerosis Complex (TSC), a multi-system disorder marked by low-grade tumors in the brain, kidneys, heart, eyes, lung and skin, arising from inherited or spontaneous germ-line mutations in either of the TSC1 or TSC2 genes. LAM can develop either in a patient with TSC (TSC-LAM) or spontaneously (S-LAM), and it is clear that the majority of LAM lesions of both forms are characterized by an inactivating mutation in either TSC1 or TSC2, as in TSC. Despite this genetic commonality, there is considerable heterogeneity in the tumor spectrum of TSC and LAM patients, the basis for which is currently unknown. There is extensive clinical evidence to suggest that the cell of origin for LAM, as well as many of the TSC-associated tumors, is a neural crest cell, a highly migratory cell type with extensive multi-lineage potential. Here we explore the hypothesis that the types of tumors that develop and the tissues that are affected in TSC and LAM are dictated by the developmental timing of TSC gene mutations, which determines the identities of the affected cell types and the size of downstream populations that acquire a mutation. We further discuss the evidence to support a neural crest origin for LAM and TSC tumors, and propose approaches for generating humanized models of TSC and LAM that will allow cell of origin theories to be experimentally tested. Identifying the cell of origin and developing appropriate humanized models is necessary to truly understand LAM and TSC pathology and to establish effective and long-lasting therapeutic approaches for these patients.

P202 Studying The Relationship Between Matrix Metalloproteinases And Lung Tissue Damage During A Clinical Exacerbation Of Cystic Fibrosis

Background Cystic Fibrosis (CF) is the commonest fatal autosomal recessive condition of Caucasians. The lung in CF is characterised by chronic bacterial colonisation, inflammation, and lung tissue destruction. Matrix Metalloproteinases (MMPs) are proteases that are expressed in inflammatory states that degrade lung matrix. Whilst MMPs are known to be raised in many inflammatory lung conditions, their role in CF is poorly understood. Aims The study aimed to compare lung function and MMP levels throughout an exacerbation. Methods Sputum samples and clinical information were obtained with written consent from 23 adult subjects with CF. Samples were collected at day 0, day 14 and week 6 of an exacerbation of CF. Samples were frozen, before Luminex bioassay and IL-8 ELISA was performed. The sputum concentration of MMP 1, 2, 3, 7, 8, 9,10,12,13 and IL-8 were measured. Results A statistically significant increase in IL-8 concentration (pg/ml) occurred between day 14 and week 6 (p = 0.0387). The concentration of MMP-9 decreased from day 0 to day 14 (p = 0.006), and then rose significantly between day 14 and week 6 (p = 0.0412). However, the concentration of MMP-9 at week 6 was significantly less than at day 0 (0.0453). A significant decrease in the concentration of MMP-8 occurred between day 0 and day 14 (p = 0.0124); and between day 0 to week 6 (p = 0.0426). Conclusions MMPs and other inflammatory markers are raised during exacerbations, and fall with treatment. High proteolytic activity may lead to a worsening lung function and contribute significantly to structural changes within the CF lung. Furthering our understanding of this diverse group of proteases could lead to potential novel therapeutic targets which could help prevent irreversible lung damage.

New treatments in development for Pseudomonas aeruginosa infections in the lungs of individuals with cystic fibrosis

New treatments in development for Pseudomonas aeruginosa infections in the lungs of individuals with cystic fibrosis Saeed S Akhand,1 Rebecca S Pettit,2 Tonia E Gardner,3 Gregory G Anderson1 1Department of Biology, Indiana University&ndash;Purdue University Indianapolis, 2Riley Hospital for Children, Indiana University Health, 3Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA Abstract: In 1989, with the discovery of the genetic mutation causing cystic fibrosis (CF), a cure for this terrible disease seemed just around the corner. Though significant progress has been made to improve the quality of life of CF patients, a remedy for CF is yet to be found. Of great concern, such bacteria as Pseudomonas aeruginosa establish chronic infections that are extremely difficult to eradicate. P. aeruginosa thrives in the CF lung environment, where it protects itself from the host inflammatory defense and contributes immensely to the lung inflammation and tissue destruction seen with the disease. Tackling and eradicating P. aeruginosa infection in the CF lung holds the key to lessen the suffering of these individuals. Unfortunately, current antibiotic regimens are insufficient to eliminate P. aeruginosa from the CF lung. In this review, we address recent drugs that are currently under development to eradicate P. aeruginosa infection in the airways of patients with CF. We discuss the P. aeruginosa infection from the perspective of CF, the shortcomings of current drugs, and the upcoming drugs that are under clinical trials and development. These new drugs and therapies hold much promise for treating recalcitrant P. aeruginosa infections and improving the lives of individuals with CF. Keywords: cystic fibrosis, orphan drugs, Pseudomonas aeruginosa infection

Senescence-associated secretory phenotype and its possible role in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD. Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can be triggered by many different mechanisms, including DNA damage and its recognition by cellular sensors, leading to the activation of cell cycle checkpoint responses and activation of DNA repair machinery. Senescence can be induced by several genotoxic factors apart from telomere attrition. When senescence induction is based on DNA damage, senescent cells display a unique phenotype, which has been termed "senescence-associated secretory phenotype" (SASP). SASP may be an important driver of chronic inflammation and therefore may be part of a vicious cycle of inflammation, DNA damage, and senescence. This research perspective aims to showcase cellular senescence with relevance to COPD and the striking similarities between the mediators and secretory phenotype in COPD and SASP.

The vascular bed in COPD: pulmonary hypertension and pulmonary vascular alterations.

The loss of pulmonary vessels has been shown to be related to the severity of pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD). The severity of hypoxaemia is also related to pulmonary hypertension and pulmonary vascular resistance in these patients, suggesting that the hypoxic condition probably plays an important role in this form of pulmonary hypertension. However, pulmonary hypertension also develops in patients with mild COPD without hypoxaemia. Oxygen supplementation therapy often fails to reverse the pulmonary hypertension in these COPD patients, thus suggesting that the pulmonary vascular alterations in those patients may involve different sites of the pulmonary vasculature or a different form of vascular remodelling. It has recently been demonstrated that pulmonary vascular remodelling, resulting in pulmonary hypertension in COPD patients, can develop independently from parenchymal destruction and loss of lung vessels. We wonder whether the changes in the lung microenvironment due to hypoxia and vessel loss have a causative role in the development of pulmonary hypertension in patients with COPD. Herein we review the pathobiological features of the pulmonary vasculature in COPD patients and suggest that pulmonary hypertension can occur with and without emphysematous lung tissue destruction and with and without loss of lung vessels.

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

Tuberculosis (TB), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. Pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. Cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. The host immunological reaction to Mycobacterium tuberculosis is implicated in driving the development of TB cavities. TB is characterized by a matrix-degrading phenotype in which the activity of proteolytic matrix metalloproteinases (MMPs) is relatively unopposed by the specific tissue inhibitors of metalloproteinases. Proteases, in particular MMPs, secreted from monocyte-derived cells, neutrophils, and stromal cells, are involved in both cell recruitment and tissue damage and may cause cavitation. MMP activity is augmented by proinflammatory chemokines and cytokines, is tightly regulated by complex signaling paths, and causes matrix destruction. MMP concentrations are elevated in human TB and are closely associated with clinical and radiological markers of lung tissue destruction. Immunomodulatory therapies targeting MMPs in preclinical and clinical trials are potential adjuncts to TB treatment. Strategies targeting patients with cavitary TB have the potential to improve cure rates and reduce disease transmission.

Unopposed Cathepsin G, Neutrophil Elastase, and Proteinase 3 Cause Severe Lung Damage and Emphysema

Cigarette smoking is a major factor for the development of pulmonary emphysema because it induces abnormal inflammation and a protease-rich local milieu that causes connective tissue breakdown of the lungs. As a result of its capacity to degrade lung tissue and the high risk of patients lacking α1-antitrypsin to develop emphysema, much interest has focused on neutrophil elastase (NE). Two similar neutrophil serine proteases (NSPs), cathepsin G and proteinase 3, coexist with NE in humans and mice, but their potential tissue-destructive role(s) remains unclear. Using a gene-targeting approach, we observed that in contrast to their wild-type littermates, mice deficient in all three NSPs were substantially protected against lung tissue destruction after long-term exposure to cigarette smoke. In exploring the underlying basis for disrupted wild-type lung air spaces, we found that active NSPs collectively caused more severe lung damage than did NE alone. Furthermore, NSP activities unleashed increased activity of the tissue-destructive proteases macrophage elastase (matrix metalloproteinase-12) and gelatinase B (matrix metalloproteinase-9). These invivo data provide, for the first time, compelling evidence of the collateral involvement of cathepsin G, NE, and proteinase 3 in cigarette smoke-induced tissue damage and emphysema. They also reveal a complex positive feed-forward loop whereby these NSPs induce the destructive potential of other proteases, thereby generating a chronic and pathogenic protease-rich milieu.

Respiratory Syncytial Virus Infections Enhance Cigarette Smoke Induced COPD in Mice

Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.

Small Angle Scattering of Fibrinogen Polymerization Kinetics and of Alpha1 Antitrypsin Interactions with Lipid Membranes

Fibrinogen and Alpha 1-Antitrypsin (A1AT) are plasma glycoproteins with different, but specific functions. A1AT has been shown to have protective roles of lung cells against emphysema, a disease characterized by lung tissue destruction [1], while fibrinogen is a major factor in the blood clotting process. Most known glycoproteins have been shown to play a role in cellular interactions but the exact role of the glycan chains is still under investigation. Previous electrophysiological measurements show that A1AT has a strong affinity to lipid bilayers perturbing the function of ion channels present in the membrane. This study was designed to investigate how protein-membrane and protein-protein interactions affect the native conformation of the protein and membrane in question. Two different glycoproteins were used for comparison purposes. For A1AT, we performed contrast-matching small-angle neutron scattering (SANS) and small angle x-ray scattering (SAXS) experiments to study the structural changes of the glycosylated form of A1AT in the presence of three different lipid membranes: POPC, POPS and DLPC. For fibrinogen, we performed dynamic light scattering (DLS) measurements to find a suitable protein concentration that would yield the reaction rate needed for a time resolved SANS study of the structural evolution of fibrinogen polymerization in solution. Guinier fits were used as a first approximation to obtain the radius of gyration (Rg) of A1AT, fibrinogen and fibrin. Pair distribution functions were used to monitor the shifts in structural parameters and Bragg peaks were used to study the structural changes of lipid vesicles. We observed that the A1AT interacts with unilamellar vesicles and that fibrin structure is affected by its polymerization rate. [1] Petrusca, et al., JBC 2010.

Lung damage after long-term exposure of adult rats to sodium fluoride.

IntroductionFluorides, when taken in amounts exceeding the standard therapeutic dosage, are regarded as toxic substances. Chronic fluorosis causes marked destruction of lung tissues. The study aimed to determine whether the effect of a chronic toxic dose of sodium fluoride on the lung of an adult male albino rat is reversible or irreversible. This was done through light and electron microscopic studies. Morphometric study was also done.Material and methodsForty adult male rats were used. The animals were divided into 3 groups: control group; group I (chronic fluorosis group) in which sodium fluoride was given daily for 3 months; and group II (recovery group) in which sodium fluoride was given daily for 3 months and after that the rats survived for another month.ResultsThe lung of group I was characterized by presence of blood and lymph congestion. Thickening of alveolar septa was also observed with rupture of septa and widening of the air spaces. The area % of collagen (1.13 ±0.5), septal wall thickness (13.47 ±6.1), and number of macrophages (5 ±2.5) increased in comparison to the control group (p ≤ 0.05). With discontinuation of sodium fluoride (group II), no much improvement was observed.ConclusionsChronic fluorosis has many pathological effects on the lung which are irreversible.

Physiology's Impact: Applying Mathematics and Advanced Technologies

How do you measure the mechanical forces generated by single cells? What are the cues that guide cell migration? What are the interactions between cells that account for cooperative behaviors among cells? To answer these and many other basic questions about biological function, we must have the

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.

Bronchoscopic Nitinol Coil Implantation: A New Lung Volume Reduction Strategy in COPD

Emphysema is a progressive, debilitating disease characterised by irreversible destruction of lung tissue. The gas trapping within the destroyed alveoli, and resultant hyperinflation, render conventional medical treatment generally of limited benefit, especially in the advanced stages of the disease. Utilisation of bronchoscopic techniques for achieving lung volume reduction has advanced over the past years. Amongst these, lung volume reduction using coils (LVRC) is a promising option. The LVRC are made from preformed Nitinol wire with shape memory. They are bronchoscopically delivered into the desired sub-segmental bronchus and recover to a pre-determined shape upon deployment. Published data so far, with endpoints being safety and feasibility, are promising. The procedure itself seems to be technically feasible and results in significant improvements in pulmonary function, exercise capacity, and quality of life sustained during the follow-up period, and with an overall acceptable safety profile. Current ongoing studies further investigate the feasibility, safety, and efficiency of LVRC. Future research is necessary in order to elucidate whether the patient selection criteria and methodology currently used are amenable to improvements, and to establish the duration of benefit and its cost-effectiveness when compared to optimal medical treatment, before applying this treatment into routine clinical practice.