scholarly journals Contribution of Dipeptidyl peptidase 4 to Nontypeable H. influenzae-induced lung inflammation in COPD

2021 ◽  
Author(s):  
Sudhir Kotnala ◽  
Yerin Kim ◽  
Charu Rajput ◽  
Hymavathi Reddyvari ◽  
Sudhir Bolla ◽  
...  
Keyword(s):  
Lung Inflammation ◽  
Inflammatory Cells ◽  
Normal Subjects ◽  
Dipeptidyl Peptidase ◽  
Chronic Obstructive ◽  
Acute Lung Inflammation ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitor ◽  
Copd Patients ◽  
Pulmonary Macrophages

Dipeptidyl peptidase 4 (DPP4) expression is increased in the lungs of chronic obstructive pulmonary disease (COPD). DPP4 is known to be associated with inflammation in various organs, including LPS-induced acute lung inflammation. Since non-typeable H. influenzae (NTHi) causes acute exacerbations in COPD patients, we examined the contribution of DPP4 in NTHi-induced lung inflammation in COPD.  Pulmonary macrophages isolated from COPD patients showed higher expression of DPP4 than the macrophages isolated from normal subjects.  In response to NTHi infection, COPD, but not normal macrophages show a further increase in the expression DPP4.  COPD macrophages also showed higher expression of IL-1β, and CCL3 responses to NTHi than normal, and treatment with DPP4 inhibitor, diprotin A attenuated this response.  To examine the contribution of DPP4 in NTHi-induced lung inflammation, COPD mice were infected with NTHi, treated with diprotin A or PBS intraperitoneally, and examined for DPP4 expression, lung inflammation and cytokine expression.  Mice with COPD phenotype showed increased expression of DPP4, which increased further following NTHi infection.  DPP4 expression was primarily observed in the infiltrated inflammatory cells.  NTHi-infected COPD mice also showed sustained neutrophilic lung inflammation and expression of CCL3, and this was inhibited by DPP4 inhibitor. These observations indicate that enhanced expression of DPP4 in pulmonary macrophages may contribute to sustained lung inflammation in COPD following NTHi infection.  Therefore, inhibition of DPP4 may reduce the severity of NTHi-induced lung inflammation in COPD.

scholarly journals Evaluation of the Efficacy of Omega-3 Fatty Acids Formulations in the Lipopolysaccharide-Induced Acute Lung Inflammation Rat Model

2021 ◽  
Author(s):  
Chandrashekhar Kocherlakota ◽  
Nagaraju Banda ◽  
Arjun Narala ◽  
Srinath Akula ◽  
Kumar S.D. Kothapalli ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Lung Inflammation ◽  
Treatment Options ◽  
Current Treatment ◽  
Ethyl Esters ◽  
Chronic Obstructive ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Acute Lung Inflammation ◽  
Severity Scores

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. The O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour later, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3 groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress like COVID-19.

scholarly journals Inflammatory cellular response to mechanical ventilation in elastase-induced experimental emphysema: role of pre-existing alveolar macrophages infiltration

2017 ◽  
Author(s):  
Anahita Rouze ◽  
Guillaume Voiriot ◽  
Elise Guivarch ◽  
Françoise Roux ◽  
Jeanne Tran Van Nhieu ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Alveolar Macrophages ◽  
Pulmonary Emphysema ◽  
Lung Inflammation ◽  
Cellular Response ◽  
Invasive Mechanical Ventilation ◽  
Inflammatory Cells ◽  
Chord Length ◽  
Lung Mechanics ◽  
Chronic Obstructive

ABSTRACTBackgroundAn excessive pulmonary inflammatory response could explain the poor prognosis of chronic obstructive pulmonary disease (COPD) patients submitted to invasive mechanical ventilation. The aim of this study was to evaluate the response to normal tidal volume (Vt) mechanical ventilation in a murine model of pulmonary emphysema, which represents the alveolar component of COPD. In this model, two time points associated with different levels of lung inflammation but similar lung destruction, were analyzed.MethodsC57BL/6 mice received a tracheal instillation of 5 IU of porcine pancreatic elastase (Elastase mice) or the same volume of saline (Saline mice). Fourteen (D14) and 21 (D21) days after instillation, mice were anesthetized, intubated, and either mechanically ventilated (MV) with a normal Vt (8 mL/kg) or maintained on spontaneous ventilation (SV) during two hours. We analyzed respiratory mechanics, emphysema degree (mean chord length by lung histological analysis), and lung inflammation (bronchoalveolar lavage (BAL) cellularity, proportion and activation of total lung inflammatory cells by flow cytometry).ResultsAs compared with Saline mice, Elastase mice showed a similarly increased mean chord length and pulmonary compliance at D14 and D21, while BAL cellularity was comparable between groups. Lung mechanics was similarly altered during mechanical ventilation in Elastase and Saline mice. Activated alveolar macrophages CD11bmid were present in lung parenchyma in both Elastase SV mice and Elastase MV mice at D14 but were absent at D21 and in Saline mice, indicating an inflammatory state with elastase at D14 only. At D14, Elastase MV mice showed a significant increase in percentage of neutrophils concomitant with a decrease in percentage of alveolar macrophages in total lung, as compared with Elastase SV mice. Furthermore, alveolar macrophages of Elastase MV mice at D14 overexpressed Gr1, and monocytes showed a trend to overexpression of CD62L, compared with Elastase SV mice.ConclusionsIn an elastase-induced model of pulmonary emphysema, normal Vt mechanical ventilation produced an increase in the proportion of pulmonary neutrophils, and an activation of alveolar macrophages and pulmonary monocytes. This response was observed only when the emphysema model showed an underlying inflammation (D14), reflected by the presence of activated alveolar macrophages CD11bmid.

Depletion of pulmonary intravascular macrophages inhibits acute lung inflammation

2004 ◽  
Vol 286 (2) ◽  
pp. L363-L372 ◽  
Author(s):  
Baljit Singh ◽  
Jacqueline W. Pearce ◽  
Lakshman N. Gamage ◽  
Kyathanahalli Janardhan ◽  
Sarah Caldwell
Keyword(s):  
Lung Inflammation ◽  
Acute Inflammation ◽  
Inflammatory Cells ◽  
Acute Lung Inflammation ◽  
Tnf Α ◽  
Highly Sensitive ◽  
In Vitro Exposure ◽  
Pulmonary Intravascular Macrophages

Pulmonary intravascular macrophages (PIMs) are present in ruminants and horses. These species are highly sensitive to acute lung inflammation compared with non-PIM-containing species such as rats and humans. There is evidence that rats and humans may also recruit PIMs under certain conditions. We investigated precise contributions of PIMs to acute lung inflammation in a calf model. First, PIMs were recognized with a combination of in vivo phagocytic tracer Monastral blue and postembedding immunohistology with anti-CD68 monoclonal antibody. Second, gadolinium chloride depleted PIMs within 48 h of treatment ( P < 0.05). Finally, PIMs contain TNF-α, and their depletion reduces cells positive for IL-8 ( P < 0.05) and TNF-α ( P < 0.05) and histopathological signs of acute lung inflammation in calves infected with Mannheimia hemolytica. The majority of IL-8-positive inflammatory cells in lung septa of infected calves were platelets. Platelets from normal cattle contained preformed IL-8 that was released upon in vitro exposure to thrombin ( P < 0.05). These novel data show that PIMs, as the source of TNF-α, promote recruitment of inflammatory cells including IL-8-containing platelets to stimulate acute inflammation and pathology in lungs. These data may also be relevant to humans due to our ability to recruit PIMs.

Detection of expiratory flow limitation during exercise in COPD patients

1997 ◽  
Vol 82 (3) ◽  
pp. 723-731 ◽  
Author(s):  
Nickolaos G. Koulouris ◽  
Ioanna Dimopoulou ◽  
Päivi Valta ◽  
Richard Finkelstein ◽  
Manuel G. Cosio ◽  
...  
Keyword(s):  
Normal Subjects ◽  
Chronic Obstructive ◽  
Flow Limitation ◽  
Expiratory Flow Limitation ◽  
Obstructive Pulmonary Disease ◽  
Normal Limits ◽  
Volume Curve ◽  
Copd Patients ◽  
Flow Volume Curve ◽  
Expiratory Flow

Koulouris, Nickolaos G., Ioanna Dimopoulou, Päivi Valta, Richard Finkelstein, Manuel G. Cosio, and J. Milic-Emili.Detection of expiratory flow limitation during exercise in COPD patients. J. Appl. Physiol. 82(3): 723–731, 1997.—The negative expiratory pressure (NEP) method was used to detect expiratory flow limitation at rest and at different exercise levels in 4 normal subjects and 14 patients with chronic obstructive pulmonary disease (COPD). This method does not require performance of forced expirations, nor does it require use of body plethysmography. It consists in applying negative pressure (−5 cmH2O) at the mouth during early expiration and comparing the flow-volume curve of the ensuing expiration with that of the preceding control breath. Subjects in whom application of NEP does not elicit an increase in flow during part or all of the tidal expiration are considered flow limited. The four normal subjects were not flow limited up to 90% of maximal exercise power output (W˙max). Five COPD patients were flow limited at rest, 9 were flow limited at one-third W˙max, and 12 were flow limited at two-thirdsW˙max. Whereas in all patients who were flow limited at rest the maximal O2 uptake was below the normal limits, this was not the case in most of the other patients. In conclusion, NEP provides a rapid and reliable method to detect expiratory flow limitation at rest and during exercise.

Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease

1983 ◽  
Vol 55 (1) ◽  
pp. 8-15 ◽  
Author(s):  
F. Bellemare ◽  
A. Grassino
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Normal Subjects ◽  
Chronic Obstructive ◽  
Cycle Duration ◽  
Inspiratory Time ◽  
Obstructive Pulmonary Disease ◽  
Transdiaphragmatic Pressure ◽  
Copd Patients ◽  
Gastric Pressure

The fatigue threshold of the human diaphragm in normal subjects corresponds to a transdiaphragmatic pressure (Pdi)-inspiratory time integral (TTdi) of about 15% of Pdimax. The TTdi of resting ventilation was measured in 20 patients with chronic obstructive pulmonary disease (COPD) and ranged between 1 and 12% of Pdimax (mean 5%). TTdi was significantly related to total airway resistance (Raw) (r = 0.57; P less than 0.05). Five of these patients were asked to voluntarily modify their TI/TT (ratio of inspiratory time to total cycle duration; from 0.33 to 0.49) so as to increase their TTdi from a control value of 8% to an imposed value of 17% of Pdimax. The imposed pattern induced a progressive decline in the high-frequency (150-350 Hz)/low-frequency (20-40 Hz) power ratio (H/L) of the diaphragm electromyogram (fatigue pattern), quantitatively similar to that seen in normal subjects breathing with similar TTdi levels. The decay in H/L was followed by a progressive fall in mean Pdi meanly due to decrease in gastric pressure swings. It is concluded that 1) the force reserve of the diaphragm in COPD patients is decreased because of a decrease in Pdimax; 2) the remaining force reserve of the diaphragm can be exhausted by even minor modifications in the breathing pattern; and 3) at a TI/TT of 0.40 our COPD patients can increase their mean Pdi 3-fold before reaching a fatiguing pattern of breathing compared with 8-fold in normal subjects.

Partitioning of work of breathing in mechanically ventilated COPD patients

1993 ◽  
Vol 75 (4) ◽  
pp. 1711-1719 ◽  
Author(s):  
M. L. Coussa ◽  
C. Guerin ◽  
N. T. Eissa ◽  
C. Corbeil ◽  
M. Chasse ◽  
...  
Keyword(s):  
Work Of Breathing ◽  
Normal Subjects ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Mechanically Ventilated ◽  
Airway Occlusion ◽  
Copd Patients ◽  
Additional Resistance ◽  
Work Done ◽  
Inspiratory Muscle Fatigue

In 10 sedated paralyzed mechanically ventilated chronic obstructive pulmonary disease (COPD) patients, we measured the inspiratory mechanical work done per breath on the respiratory system (WI,rs). We measured the tracheal and esophageal pressures to assess the lung (L) and chest wall (W) components of WI and used the technique of rapid airway occlusion during constant-flow inflation to partition WI into static work [Wst, including work due to intrinsic positive end-expiratory pressure (WPEEPi)], dynamic work due to airway resistance, and the additional resistance offered by the respiratory tissues. Although the patients were hyperinflated, the slope of the static volume-pressure relationships of the lung did not decrease with inflation volume up to 0.8 liter. WI,W was similar in COPD patients and normal subjects. All components of WI,L were higher in COPD patients. The increase in Wst,rs was due entirely to WPEEPi. Our data suggest that, during spontaneous breathing, COPD patients would probably develop inspiratory muscle fatigue, unless continuous positive airway pressure were applied to reduce WPEEPi.

scholarly journals Effects of fluticasone propionate inhalation on levels of arachidonic acid metabolites in patients with chronic obstructive pulmonary disease

2001 ◽  
Vol 10 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Gert T. Verhoeven ◽  
Ingrid M. Garrelds ◽  
Henk C. Hoogsteden ◽  
Freek J. Zijlstra
Keyword(s):  
Arachidonic Acid ◽  
Fluticasone Propionate ◽  
Controlled Trial ◽  
Inflammatory Cells ◽  
Control Group ◽  
Chronic Obstructive ◽  
Clinical Effects ◽  
Paired Data ◽  
Cell Numbers ◽  
Copd Patients

Background: In smoking COPD patients the bronchoalveolar lavage (BAL) fluid contains high numbers of inflammatory cells. These cells might produce arachidonic acid (AA) metabolites, which contribute to inflammation and an increased bronchomotor tone.Aims: To investigate levels of AA metabolites in BAL fluid, before and after inhaled glucocorticoid therapy: fluticasone propionate (FP) 1mg per day, or placebo.Methods: A double-blind placebo controlled trial lasting six months. COPD patients were selected by clinical criteria and the presence of bronchial hyperresponsiveness (BHR). Lung function was recorded and in BAL fluid we counted cell numbers and measured LTB4, LTC4/D4/E4, PGE2, 6kPGF1α , PGF2α and TxB2. A control group consisted of asymptomatic smokers(n=6).Results: Paired data were obtained from 9 FP treated and 11 placebo patients. BAL cells were almost exclusively alveolar macrophages. In patients and controls both cellularity and levels of AA metabolites were equal. Cell numbers did not change after treatment. Statistically significant decreases after FP therapy were noticed for PGE2(30%), 6kPGF1α (41%) and PGF2α (54%).Conclusions: In COPD, the capability of inflammatory cells to produce certain AA metabolites was decreased after inhaled FP treatment. This result is discussed in its relation to clinical effects, the influence of smoking, and the results of an earlier, similar study in asthma patients.

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