Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium.

BACKGROUND: The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. OBJECTIVES: To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. METHODS: Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in patients with mild/moderate (n = 17), severe/very severe (n = 16) stable COPD, control smokers (n = 16), control non-smokers (n = 9), in mild asthma (n = 9) and in peripheral airways from COPD patients (n = 15) and control smokers (n = 15). Interleukin (IL)-8 and MAPK mRNA was measured in stimulated 16HBE cells. RESULTS: No significant differences in p-p38 MAPK, p-JNK or p-ERK1/2 expression were seen in bronchial biopsies and peripheral airways between COPD and control subjects. Asthmatics showed increased submucosal p-p38 MAPK expression compared to COPD patients (p < 0.003) and control non-smokers (p < 0.05). Hydrogen peroxide (H2O2), cytomix (tumour necrosis factor-α + IL-1ß + interferon-γ) and lipopolysaccharide (LPS) upregulated IL-8 mRNA at 1 or 2 h. p38 MAPKα mRNA was significantly increased after H2O2 and LPS treatment. JNK1 and ERK1 mRNA were unchanged after H2O2, cytomix or LPS treatments. CONCLUSION: p-p38 MAPK expression is similar in stable COPD and control subjects but increased in the bronchi of mild asthmatics compared to stable COPD patients. p38 MAPK mRNA is increased after bronchial epithelial challenges in vitro. These data together suggest a potential role for this MAPK in Th2 inflammation and possibly during COPD exacerbations.

Predicting Response to In-Hospital Pulmonary Rehabilitation in Individuals Recovering From Exacerbations of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Predicting the response to pulmonary rehabilitation (PR) could be valuable in defining admission priorities. We aimed to investigate whether the response of individuals recovering from a COPD exacerbation (ECOPD) could be forecasted using machine learning approaches. METHOD: This multicenter, retrospective study recorded data on anthropometrics, demographics, physiological characteristics, post-PR changes in six-minute walking distance test (6MWT), Medical Research Council scale for dyspnea (MRC), Barthel Index dyspnea (BId), COPD assessment test (CAT) and proportion of participants reaching the minimal clinically important difference (MCID). The ability of multivariate approaches (linear regression, quantile regression, regression trees, and conditional inference trees) in predicting changes in each outcome measure has been assessed. RESULTS: Individuals with lower baseline 6MWT, as well as those with less severe airway obstruction or admitted from acute care hospitals, exhibited greater improvements in 6MWT, whereas older as well as more dyspnoeic individuals had a lower forecasted improvement. Individuals with more severe CAT and dyspnea, and lower 6MWT had a greater potential improvement in CAT. More dyspnoeic individuals were also more likely to show improvement in BId and MRC. The Mean Absolute Error estimates of change prediction were 44.70m, 3.22 points, 5.35 points, and 0.32 points for 6MWT, CAT, BId, and MRC respectively. Sensitivity and specificity in discriminating individuals reaching the MCID of outcomes ranged from 61.78% to 98.99% and from 14.00% to 71.20%, respectively. CONCLUSION: While the assessed models were not entirely satisfactory, predictive equations derived from clinical practice data might help in forecasting the response to PR in individuals recovering from an ECOPD. Future larger studies will be essential to confirm the methodology, variables, and utility.

Balance performance in patients with post-acute COVID-19 compared to patients with an acute exacerbation of chronic obstructive pulmonary disease and healthy subjects.

COVID-19 leaves important sequelae in patients, not only in those who had the experience of a critical illness but also in patients with severe form. Understanding the impairments allows us to target rehabilitation to patients' real needs; balance impairments are an assumed sequela of COVID-19, but no study has specifically evaluated balance performance in these patients. Their performance was compared to that of patients with a pulmonary disease that leads to systemic diseases, such as patients with an acute exacerbation of chronic obstructive pulmonary disease (PwAECOPD), and of healthy subjects. A total of 75 subjects were assessed: 25 patients with COVID-19 (PwCOVID) with a severe form in the acute phase, 25 PwAECOPD and 25 healthy subjects sex- and age-matched. A stabilometric platform was used to evaluate static balance, both with eyes open and closed, while the dynamic balance was assessed with the Mini-BESTest and the Timed Up and Go test. When compared to healthy subjects, results showed that PwCOVID had worse performance in both static (P < 0.005) and dynamic (P < 0.0001) balance, with a large effect size in all measures (>0.8). Moreover, PwCOVID showed similar results to those of PwAECOPD. In conclusion, PwCOVID showed a balance deficit in both dynamic and static conditions. Therefore, as for PwAECOPD, they should require not only respiratory rehabilitation but also balance and mobility physiotherapy to prevent today's PwCOVID from becoming tomorrow's fallers.

The Coronavirus Footprint on Dual-Task Performance in Post-Acute Patients after Severe COVID-19: A Future Challenge for Rehabilitation.

Recent studies suggest that also the non-critical form of COVID-19 infection may be associated with executive function impairments. However, it is not clear if they result from cognitive impairments or by COVID-19 infection per se. We aimed to investigate if patients in the post-acute stage of severe COVID-19 (PwCOVID), without manifest cognitive deficits, reveal impairments in performing dual-task (DT) activities compared to healthy controls (HS). We assessed balance in 31 PwCOVID vs. 30 age-matched HS by stabilometry and the Timed Up and Go (TUG) test with/without a cognitive DT. The DT cost (DTC), TUG test time and sway oscillations were recorded; correct cognitive responses (CCR) were calculated to evaluate cognitive performance. Results show a significant difference in overall DT performance between PwCOVID and HS in both stabilometry (p < 0.01) and the TUG test (p < 0.0005), although with similar DTCs. The main difference in the DTs between groups emerged in the CCR (effect size > 0.8). Substantially, PwCOVID gave priority to the motor task, leaving out the cognitive one, while HS performed both tasks simultaneously. Our findings suggest that PwCOVID, even without a manifest cognitive impairment, may present a deficit in executive function during DTs. These results encourage the use of DTs and CCR in PwCOVID.

Pulmonary rehabilitation in patients with interstitial lung diseases: Correlates of success.

BACKGROUND AND AIM: Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting. METHODS: Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated. Six minute walking distance (6MWT), body weight-walking distance product tests, dyspnoea and arterial blood gases were assessed at admission and discharge. Differences in post rehabilitation changes in outcome measures as function of baseline characteristics were evaluated. RESULTS: After rehabilitation, patients showed improvements in all outcome measures (p < 0.05), regardless of the underlying diagnosis or disease severity. Patients needing oxygen therapy at rest showed reduced benefits. Baseline 6MWD inversely correlated with its changes at discharge. Non-significant greater benefits after rehabilitation were found in IPF patients under antifibrotic therapy. In a subset of 50 patients assessed on average 10.3 ± 3.5 months after discharge, the benefits in 6MWD were not maintained (312.9 ± 139.4, 369.7 ± 122.5 and 310.8 ± 139.6 m at admission, discharge and follow up respectively: p < 0.0001). CONCLUSION: Pulmonary rehabilitation may improve dyspnoea, exercise capacity and fatigue in patients with ILD of different aethiologies and level of severity. The long-term effects need to be established.

Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H2O2. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H2O2 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COPD.

Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease.

BACKGROUND: Reactive nitrogen species, formed via the reaction of nitric oxide (NO) with superoxide anion and via (myelo)peroxidase-dependent oxidation of NO(2)(-), have potent proinflammatory and oxidizing actions. Reactive nitrogen species formation and nitrosative stress are potentially involved in chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVES: To investigate the expression of markers of nitrosative stress, including nitrotyrosine (NT), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), myeloperoxidase (MPO), and xanthine oxidase (XO) in bronchial biopsies and bronchoalveolar lavage from patients with mild to severe stable COPD compared with control groups (smokers with normal lung function and nonsmokers). METHODS: The expression of NT, iNOS, eNOS, MPO and XO in the bronchial mucosa and bronchoalveolar lavage of patients was measured by using immunohistochemistry, Western blotting, and ELISA and correlated with the inflammatory cell profile. RESULTS: Patients with severe COPD in stable phase had higher numbers of NT(+) and MPO(+) cells in their bronchial submucosa compared with mild/moderate COPD, smokers with normal lung function, and nonsmokers (P < .01). iNOS(+) and eNOS(+) but not XO(+) cells were significantly increased in smokers with COPD or normal lung function compared with nonsmokers (P < .05 and P < .01, respectively). In patients with COPD, the number of MPO(+) cells was significantly correlated with the number of neutrophils (r = +0.61; P < .0025) in the bronchial submucosa. Furthermore, the number of NT(+) and MPO(+) cells was negatively correlated with postbronchodilator FEV(1). CONCLUSION: These data suggest that nitrosative stress, mainly mediated by MPO and neutrophilic inflammation, may contribute to the pathogenesis of severe COPD.

Increased macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis.

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are two CC chemokines that induce lymphocyte migration. MIP-1alpha preferentially mediates chemotaxis of CD8 rather than CD4 lymphocytes, whereas the reverse is true for MIP-1beta. Both these chemokines recognize CCR5 as a cellular receptor in T lymphocytes and alveolar macrophages. We measured the concentrations of MIP-1alpha and MIP-1beta in bronchoalveolar lavage fluid (BALF) of 30 subjects affected by different stages of pulmonary sarcoidosis and 18 healthy normal subjects. We also evaluated the expression of CCR5 in alveolar macrophages and lymphocytes. The BALF concentrations of MIP-1alpha were significantly increased only in Stage II and III sarcoidosis. On the contrary, the concentrations of MIP-1beta were significantly increased at all stages. A striking increase of CCR5 expression was observed in both lymphocytes and macrophages of all patients, along with a trend to decreased positivity from Stage I to III of the disease. The MIP-1beta concentrations correlated with the number of total (r = 0.65, p = 0.0001) and both CD4 (r = 0.64, p = 0.0001) and CD8 (r = 0.62, p = 0.0001) lymphocytes; on the contrary, the MIP-1alpha concentrations correlated only with CD8 lymphocytes (r = 0.45, p = 0.002). Finally, significant negative correlations were observed between the neutrophil percentage and CCR5 expression in alveolar macrophages (r = -0.53, p = 0.005) and lymphocytes (r = -0.43, p = 0.01). Our results help to explain the mechanism of CD4 and CD8 recruitment and the possible involvement of CC chemokines in the fibrotic progression of sarcoidosis.