Long non-coding RNA LINC01194 promotes the inflammatory response and apoptosis of lipopolysaccharide-treated MLE-12 cells through the miR-203a-3p/MIP-2 axis.

Acute lung injury (ALI) induced by bacteria lipopolysaccharide (LPS) is characterized by the upregulation of the apoptosis rate of tissue cells and aggravation of inflammatory response. Although many studies have focused on the pathogenesis of this disease, its mechanism remains unknown. This study examined the regulatory role of long non-coding RNA (lncRNA) LINC01194 in the progression of ALI through various bioinformatics analyses and experimental work, including ELISA assay, dual-luciferase reporter assay, biotinylated RNA pull-down assay, and Western blot analysis. The result showed that the LINC01194 was overexpressed in the ALI-induced mice model. We observed a significant upregulation of LINC01194 in LPS-treated mouse lung epithelial type II cells (MLE-12 cells) after 24 h of induction. Bioinformatics analysis, ELISA assay, quantitative reverse transcription polymerase chain reaction analysis, biotinylated RNA pull-down assay, apoptosis test, and Western blot analysis demonstrated that the LINC01194 could act as a microRNA (miR) miR-203a-3p sponge to activate the inflammatory response in LPS-induced ALI model through post-transcriptional upregulation of macrophage inflammatory protein (MIP-2). We showed that LINC01194 regulates the inflammatory response and apoptosis of LPS-induced mice and MLE-12 cells via the miR-203a-3p/MIP-2 axis. LINC01194 could be a potential biomarker for early diagnosis and the treatment of ALI.

Differential sensitivities of pyrogenic chemokine fevers to CC chemokine receptor 5 antibodies.

Macrophage inflammatory protein (MIP)-1beta and RANTES (regulated on activation, normal T-cells expressed and secreted) are members of the CC-family of chemokines. Although these two peptides are structurally and functionally related to one another, each exhibits distinct features, which allows it to independently regulate specific aspects of the host inflammatory response. They evoked intense and functionally different febrile responses when applied directly on pyrogen-sensitive cells located in the in the preoptic area of the anterior hypothalamus (POA). The present experiments were carried out to test the central role of CCR5, a functional receptor for MIP-1beta and RANTES, in the febrile responses induced by these chemokines when injected directly into the POA. The microinjection of an equimolecular dose (50 pg) of either MIP-1beta or RANTES into the POA induced a rapid onset; monophasic fever in rats that persisted for a long period. The microinjection of 2.0 microg specific neutralizing antibodies against CCR5 (anti-CCR5) into the POA fails to affect the effects on body temperature induced by MIP-1beta. However, pretreatment with the same dose of anti-CCR5 suppressed the febrile response induced by RANTES given at the same site. The microinjection of control IgG or anti-CCR5 does not affect basal temperature, when administered alone at the same hypothalamic site. The present experiments show that hypothalamic CCR5 are functionally involved in the febrile response induced by RANTES, but not by MIP-1beta. They also suggest the existence of functionally different components in the presumptive primary locus of the thermoregulatory controller, in which both chemotactic cytokines, together other mediators, could play a relevant role in the complex process of fever pathogenesis.

Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010.

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflammatory cytokine, it is now recognised that hMIP-1 alpha has additional effects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utility of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-10010. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 micrograms/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related increase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of baseline. no measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extremely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic analysis revealed that serum concentrations of BB-10010 were detectable using doses of > or = 10 micrograms/kg i.v. or > or = 30 micrograms/kg s.c., and that a single s.c. injection resulted in sustained plasma levels over a 24 h period. These preliminary studies have confirmed the safety and tolerability of BB-10010 using a dose range up to 300 micrograms/kg. Further clinical studies are ongoing to determine the biological effects and to investigate the potential myeloprotective properties using a variable dose range and schedule of BB-10010 in combination with cytotoxic chemotherapy.

A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy.

BB-10010 is a variant of the human form of macrophage inflammatory protein-1alpha (MIP-1alpha), which has been shown in mice to block the entry of hematopoietic stem cells into S-phase and to increase their self-renewal capacity during recovery from cytotoxic damage. Its use may constitute a novel approach for protecting the quality of the stem cell population and its capacity to regenerate after periods of cytotoxic treatment. Thirty patients with locally advanced or metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate the potential myeloprotective effects of a 7-day regimen of BB-10010 administered to patients receiving six cycles of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were randomized, 10 receiving 100 microgram/kg BB-10010, 11 receiving 30 microgram/kg BB-10010, and nine control patients receiving no BB-10010. BB-10010 was well-tolerated in all patients with no severe adverse events related to the drug. Episodes of febrile neutropenia complicated only 4% of the treatment cycles and there was no difference in incidence between the treated and nontreated groups. Studies to assess the generation of progenitor cells in long-term bone marrow cultures were performed immediately preceding chemotherapy and at the end of six dosing cycles in 18 patients. Circulating neutrophils, platelets, CD 34(+) cells, and granulocyte/macrophage colony-forming cell (GM-CFC) levels were determined at serial time points in cycles 1, 3, and 6. The results showed similar hemoglobin and platelet kinetics in all three groups. On completion of the six treatment cycles, the average pretreatment neutrophil levels were reduced from 5.3 to 1.7 x 10(9)/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 x 10(9)/L in the 30/100 microgram/kg BB-10010 groups, respectively. Relative to their pretreatment values, 50% of the patients receiving BB-10010 completed the treatment with neutrophil values significantly higher than any of the controls (P = .02). Mobilization of GM-CFC was enhanced by BB-10010 with an additional fivefold increase over that generated by chemotherapy alone, giving a maximal 25-fold increase over pretreatment values. Bone marrow progenitor assays before and after this standard regimen of chemotherapy indicated little long-term cumulative impairment to recovery from chemotherapy. Despite the limited cumulative damage to the bone marrow, which may have minimized the protective value of BB-10010 during this regimen of chemotherapy, better recovery of neutrophils in the later treatment cycles with BB-10010 was indicated in a number of patients.