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BACKGROUND AND OBJECTIVE: The immune system plays an important role in non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the infiltration patterns of CD4(+) and CD8(+) T cells in NSCLC and to analyze their relation to COPD, smoking status and other clinicopathologic variables. MATERIALS AND METHODS: Lung tissue specimens from 50 patients who underwent surgery for NSCLC (stages I-III) and 10 control group subjects were analyzed immunohistochemically. RESULTS: NSCLC patients had a greater number of CD4(+) and CD8(+) T cells infiltrating the lung tissue than the control group (P=0.001) with predominant infiltration in the tumor stroma. We found a significant association between the number of total and tumor stroma-infiltrating CD4(+) and CD8(+) T cells, and smoking status (P<0.05). There were more CD8(+) T cells in the tumor stroma and fewer in the tumor islets in NSCLC patients with COPD as compared to NSCLC patients without COPD (P<0.05). However, there was no such association between CD4(+) T cells and COPD status. A high level of CD8(+) T cell infiltration in the tumor stroma was independently associated with the coexistence of COPD in multivariate analysis (P<0.05). CONCLUSIONS: According to our data, COPD but not smoking seems to be associated with higher infiltration of CD8(+) T cells in the tumor stroma of patients with NSCLC. It allows us to hypothesize that NSCLC patients with coexisting COPD may have a more favorable outcome due to anticancer properties of stromal CD8(+) T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumar/imunologia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/complicações , Feminino , Humanos , Pulmão/imunologia , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Adulto JovemRESUMO
The present study aimed to investigate the effect of a H2S donor, GYY 4137, on human pulmonary arteries and whether low-frequency ultrasound (20 kHz, 4 W/cm2) inhibits GYY 4137 contractions. Functional studies were conducted on human and rat pulmonary arteries mounted on microvascular myographs. We placed an ultrasonic gadget in the tissue organ bath to insonate the arteries with low-frequency ultrasound. To measure the effect of the low-frequency ultrasound on the entrance of extracellular Ca2+, the preparations were placed in a Ca2+-free solution, and the thromboxane agonist, U46619, and extracellular calcium were added in the presence of insonation. In isolated human pulmonary arteries, GYY 4137 induced contractions, which were most pronounced in the arteries contracted with the thromboxane analogue, U46619. The transient GYY4137 contractions were reversed by low-frequency ultrasound, a blocker of KV7 channels, XE-991 (10 µM), and glibenclamide (1 µM), a blocker of ATP-sensitive channels. Low-frequency ultrasound also inhibited the contractions induced by the smooth muscle entrance of increasing extracellular calcium concentrations. The present findings show that GYY 4137 can cause a transient contraction of pulmonary arteries in human arteries. GYY 4137 alone does not cause significant vascular contraction in rat lung arteries, but it contracts rat lung arteries precontracted with U46619. The transient contractions induced by GYY 4137 can be inhibited by low-frequency ultrasound, probably by counteracting the influx of external Ca2+. The effect of low-frequency ultrasound counteracts contraction in pulmonary arteries; therefore, a possibility could be to develop a larger device allowing treatment of patients with pulmonary hypertension.
Assuntos
Morfolinas , Músculo Liso Vascular , Compostos Organotiofosforados , Artéria Pulmonar , Humanos , Ratos , Animais , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Cálcio/farmacologia , Tromboxanos/farmacologiaRESUMO
We tested the effect of low-frequency ultrasound (LUS, 20 kHz, 4 W/cm2) on the function of rat mesentery and human pulmonary arteries with wire myography. The vessels were induced to contract with either noradrenaline or physiologic saline solution (PSS) with a high potassium concentration (KPSS) and then incubated with capsaicin (2.1â¯×â¯10-7 M, TRPV1 [transient receptor potential vanilloid 1] activator), dopamine (1â¯×â¯10-4 M, dopamine and α2-receptor activator), or fenoldopam (dopamineA1 receptor agonist, 1â¯×â¯10-4 M) with and without glibenclamide (1 µM, KATP [adenosine triphosphate {sensitive potassium channel (ATP)}-sensitive potassium channel] inhibitor and α2-receptor modulator), and insonated. Vessels were incubated in Ca2+-free PSS and induced to contract with added extracellular Ca2+ and noradrenaline. Pulmonary arteries were induced to contract with KPSS and dopamine. Then the vessels were insonated. LUS inhibited the influx of external Ca2+, inhibited the dopamine-induced vasoconstriction in the KPSS (glibenclamide reversible), reduced the capsaicin-induced vasorelaxation, increased the gentamicin-induced vasorelaxation and increased the dopamine-induced contraction in the KPSS in human pulmonary arteries.
Assuntos
Mesentério/efeitos dos fármacos , Mesentério/efeitos da radiação , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/efeitos da radiação , Ondas Ultrassônicas , Animais , Humanos , Miografia , Ratos , Ratos WistarRESUMO
BACKGROUND: Different subsets of tumor infiltrating T lymphocytes are believed to play essential role in the immune response to cancer cells. The data of these cells in NSCLC are relatively rare and controversial therefore we aimed to evaluate the infiltration patterns of Foxp3 + CD4+, CD4+ and CD8+ T cells in NSCLC and to analyze their relations to survival. METHODS: Lung tissue specimens from 80 newly diagnosed and untreated patients who underwent surgery for NSCLC (stages I-III), and 16 control group subjects, who underwent surgery due to recurrent spontaneous pneumothorax, were analyzed. Foxp3 + CD4+, CD4+ and CD8+ T cells in tumor stroma and islets were evaluated immunohistochemically. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 20.0. RESULTS: Tumor infiltrating CD4+, CD8+ T cells were associated with neither overall survival nor disease-free survival. The presence of high tumor stroma infiltrating Foxp3 + CD4+ T cells was independently associated with improved NSCLC patients overall survival (P < 0.05). CONCLUSIONS: Our study demonstrated that tumor infiltrating Foxp3 + CD4+ T cells are associated with improved NSCLC patients' survival. In addition our findings highlight a tendency of high CD4+/CD8+ and CD8+/Foxp3 + CD4+ T cells ratio in prolonged NSCLC patients' survival.
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BACKGROUND AND PURPOSE: The intermediate conductance calcium/calmodulin-regulated K+ channel KCa 3.1 produces hyperpolarizing K+ currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl- and fluid movements. We investigated whether a deficiency in KCa 3.1 (KCa 3.1-/- ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. EXPERIMENTAL APPROACH: An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and KCa 3.1-/- mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells (PAEC). KEY RESULTS: In wt mice, GSK1016790A decreased right ventricular and systemic pressure leading to a fatal circulatory collapse that was accompanied by increased protein permeability, lung haemorrhage and fluid extravasation. In contrast, KCa 3.1-/- mice exhibited a significantly smaller drop in pressure to GSK1016790A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK1016790A-induced relaxation of pulmonary arteries of KCa 3.1-/- mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and KCa 3.1-/- mice, which co-activated KCa 3.1 and disrupted membrane resistance in wt PAEC, but not in KCa 3.1-/- PAEC. CONCLUSIONS AND IMPLICATIONS: Our findings show that a genetic deficiency of KCa 3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4 channels. Therefore, inhibition of KCa 3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.