Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation.

Interleukin-8 (IL-8; CXCL8) is a cytokine of the CXC chemokine family that is involved in neutrophil recruitment and activation. In addition, IL-8 has been implicated in a wide variety of other processes, including angiogenesis and metastasis in lung cancer. Lung adenocarcinoma and muco-epidermoid carcinoma cells produce substantial amounts of IL-8, and express both CXCR1 and CXCR2 IL-8 receptors. We hypothesized that IL-8 stimulates proliferation of non-small cell lung cancer cells, involving transactivation of the epidermal growth factor receptor (EGFR). The EGFR plays a central role in regulating cell proliferation and it has been therefore implicated in lung cancer. Both EGFR ligands and transactivation of the receptor may lead to downstream signalling events, including mitogen-activated protein kinase (MAPK) activation. Transactivation of the EGFR has been shown to occur in response to ligands of various G-protein coupled receptors (GPCRs) and involves metalloproteinase-mediated release of membrane bound EGFR ligands. The aim of the present study was to investigate the effect of IL-8 on proliferation of lung adenocarcinoma and muco-epidermoid carcinoma cells, and to explore the mechanisms leading to this proliferation in two different non-small cell lung cancer cell lines (A549 and NCI-H292). In both NSCLC cell lines, we observed that IL-8 stimulates epithelial cell proliferation in a dose-dependent manner. The ability of IL-8 to increase cell proliferation was blocked both by an inhibitor of EGFR tyrosine kinase, by a specific anti-EGFR blocking antibody and by a panmetalloproteinase inhibitor. Similar results were obtained using the GPCR inhibitor pertussis toxin. Inhibition of the MAPK p42/44 (ERK1/2) also blocked the mitogenic effect of IL-8, while a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation. These results suggest that IL-8 increases cell proliferation in NSCLC cell lines via transactivation of the EGFR and that this mechanism involves metalloproteinase activity.

Captopril plus losartan in early post-infarction. Neurohormonal effects: a pilot study.

BACKGROUND: Suppression of the formation of angiotensin II (A II) is thought to be a major contributor to the hemodynamic response to angiotensin-converting enzyme inhibition (ACE-inhibitor) therapy. However, during ACE-inhibitor treatment, A II plasma levels may also recover through tissue chymase. This study has attempted to verify the feasibility, safety and tolerability of a combined treatment using captopril (75 mg/day) and losartan (25 mg/day), and to ascertain its ability to reduce the formation and action of A II in the early post-infarction phase of reperfused anterior myocardial infarction (AMI). METHOD: Forty-four patients hospitalized for suspected AMI within 4 hours of the onset of symptoms, who were suitable for thrombolysis (first episode), in Killip class I-II, reperfused, treated with 75 mg/day of captopril within 3 days of admission and with a blood pressure level of more than 120 mmHg, were randomized (single-blind) into two groups that were similar with regard to age, sex, blood pressure, CK peak, ejection fraction, end-systolic volume and risk factors. Group A (22 subjects: 6 women/16 men) received captopril (75 mg/day) and placebo, while group B (22 subjects: 5 women/17 men) was given captopril (75 mg/day) plus losartan, initially at 12.5 mg and then at 25 mg/day thereafter (BP > 110 mmHg). Norepinephrine (NE) and A II plasma levels were measured on the third and tenth day after admission. RESULTS: Ten days after admission, group B (captopril plus losartan) showed a significant decrease in blood pressure (BP) on an intragroup level (p < 0.001) as well as in comparison with group A (p < 0.001), with values of 108 + 6.4 and 118 + 11 mmHg respectively. At the same time interval, NE and A II values did not show significant differences within or between groups. CONCLUSIONS. For the first time, our data suggest that a combined captopril-losartan treatment is feasible and that it has no particular side effects. In addition, it shows no significant increase of A II that would be produced by losartan alone.

[Is the reduction of the plasma levels of endothelin in the acute and sub-acute stage of myocardial infarct one of the beneficial effects of early treatment with ace inhibitors?]. / La riduzione dei livelli plasmatici dell'endotelina nelle fasi acute e sub-acute dell'infarto miocardico e uno degli effetti benefici del precoce trattamento con ace-inibitori?

BACKGROUND: Studies showed that endothelin-1 (ET-1) was increased in the acute myocardial infarction (AMI). Experimental studies reported that captopril was able to reduce ET-1 secretion. In addition increased levels of ET-1 were reported as a negative prognostic index. The study was aimed to verify whether captopril was able to reduce plasma ET-1 levels in the acute and subacute phases of AMI. METHODS: Forty five patients, hospitalized for suspected anterior AMI within 4 h since the onset of symptoms, suitable for thrombolysis (first episode), in Killip class 1-2, were randomized (double blind) into two groups: Group A (23 patients, pts), 7 females and 16 males, received captopril 6.25 mg orally (as first dose) 2-4 h after starting thrombolysis, and the doses of captopril were successively increased up to 25 mg every 8 h. Group B: (22 pts), 5 females and 17 males, received placebo after thrombolysis. All the patients met the reperfusion criteria. RESULTS: The two groups were similar for age, sex, CK peak, ejection fraction, end systolic volume and risk factors. Plasma ET levels were checked on admission, and 2, 12, 24, 48, 72 hours, after starting thrombolysis. Mean concentrations of ET +/- SD: Group A: basal 1.50 +/- 0.67, at 2 h 2.31 +/- 1.24, 12 h 1.84 +/- 1.45, 24 h 1.30 +/- 0.72, 48 h 0.95 +/- 0.50, 72 h 0.60 +/- 0.15 fmol/ml (p < 0.001). Group B: basal 1.58 +/- 0.83, at 2 h 2.38 +/- 1.35, 12 h 2.33 +/- 1.71, 24 h 1.80 +/- 1.41, 48 h 1.46 +/- 0.88, 72 h 0.93 +/- 0.44 fmol/ml (p < 0.001). Difference between the two groups was significant at 48 h (p < 0.05), and 72 h (p < 0.001). CONCLUSIONS: Our data suggest that captopril affects plasma endothelin levels in the acute and subacute phases of AMI. In addition, our results seem to be an additional support to the beneficial effects of early captopril treatment in patients with AMI.

Nerve growth factor in rat glioma cells.

We have shown that rat glioma tumors contain a protein that crossreacts with antibody against mouse 2.5S nerve growth factor prepared in rabbit in microcomplement fixation assays and has analogous isoelectric points to all the hybrids of 2.5S nerve growth factor (a dimer). Partially purified protein preparations from gliomas cause chick dorsal root ganglia to extend neurites in the nerve growth factor assay and cause morphological differentiation of mouse neuroblastoma cells. We conclude that the rat glioma protein is homologous to mouse salivary nerve growth factor and suggest the possibility that glial nerve growth factor plays a role in neuronal development and regeneration.