Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.

Despite the emergence of translational control pathways as mediators of nociceptive sensitization, effector molecules and mechanisms responsible for modulating activity in these pathways in pain conditions are largely unknown. We demonstrate that two major algogens, the cytokine interleukin 6 (IL-6) and the neurotrophin nerve growth factor (NGF), which are intimately linked to nociceptive plasticity across preclinical models and human pain conditions, signal primarily through two distinct pathways to enhance translation in sensory neurons by converging onto the eukaryotic initiation factor (eIF) eIF4F complex. We directly demonstrate that the net result of IL-6 and NGF signaling is an enhancement of eIF4F complex formation and an induction of nascent protein synthesis in primary afferent neurons and their axons. Moreover, IL-6-and NGF-induced mechanical nociceptive plasticity is blocked by inhibitors of general and capdependent protein synthesis. These results establish IL-6-and NGF-mediated cap-dependent translation of local proteins as a new model for nociceptive plasticity.

Lung carcinogenesis is a complex process involving the acquisition of genetic mutations that confer cancer development and the malignant phenotype, and is critically linked to apoptosis resistance, unregulated proliferation, invasion, metastasis, and angiogenesis. Epithelial mesenchymal transition (EMT) in cancer is an unregulated process in a host environment with deregulated inflammatory response that impairs cell-mediated immunity and permits cancer progression. Given the immunosuppressive tumor environment, strategies to reverse these events by stimulating host immune responses are an important area of investigation. Cyclooxygenase 2 (COX-2) and its downstream signaling pathways are potential targets for lung cancer chemoprevention and therapy. Clinical trials are underway to evaluate COX-2 inhibitors as adjuvants to chemotherapy in patients with lung cancer and to determine efficacy in prevention of bronchogenic carcinoma. The understanding of molecular mechanisms involved in inflammation and lung carcinogenesis provide insight for new drug development that target reversible, non-mutational events in the chemoprevention and treatment of lung cancer.

Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer.

Background In most individuals, injury results in activation of peripheral nociceptors (pain-sensing neurons of the peripheral nervous system) and amplification of central nervous system (CNS) pain pathways that serve as a disincentive to continue harmful behaviour; however, this may not be the case in some developmental disorders that cause intellectual disability (ID). Moreover, individuals affected by ID disorders may initiate self-injurious behaviour to address irritating or painful sensations. In normal individuals, a negative feedback loop decreases sensation of pain, which involves descending inhibitory neurons in the CNS that attenuate spinal nociceptive processing. If spinal nociceptive signalling is impaired in these developmental disorders, an exaggerated painful stimulus may be required in order to engage descending anti-nociceptive signals. Methods Using electronic databases, we conducted a review of publications regarding the incidence of chronic pain or altered pain sensation in ID patients or corresponding preclinical models. Results There is a body of evidence indicating that individuals with fragile X mental retardation and/or Rett syndrome have altered pain sensation. These findings in humans are supported by mechanistic studies using genetically modified mice harbouring mutations consistent with the human disease. Thus, once self-injurious behaviour is initiated, the signal to stop may be missing. Several developmental disorders that cause ID are associated with increased incidence of gastroesophageal reflux disease (GERD), which can cause severe visceral pain. Individuals affected by these disorders who also have GERD may self-injure as a mechanism to engage descending inhibitory circuits to quell visceral pain. In keeping with this hypothesis, pharmacological treatment of GERD has been shown to be effective for reducing self-injurious behaviour in some patients. Hence, multiple lines of evidence suggest aberrant nociceptive processing in developmental disorders that cause ID. Conclusions There is evidence that pain pathways and pain amplification mechanisms are altered in several preclinical models of developmental disorders that cause ID. We present hypotheses regarding how impaired pain pathways or chronic pain might contribute to self-injurious behaviour. Studies evaluating the relationship between pain and self-injurious behaviour will provide better understanding of the mechanisms underlying self-injurious behaviour in the ID population and may lead to more effective treatments.

Background: Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for ex vivo transduction of human DC in order to assess intratumoral administration in late stage human lung cancer.

Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins and thromboxanes from free arachidonic acid. Increasing evidence suggests that COX-2 plays a role in tumorigenesis. A variety of stimuli induce COX-2 and it is overexpressed in many tumors, including non-small cell lung cancer (NSCLC). We studied the regulation of COX-2 expression in immortalized human bronchial epithelial cells (HBECs) by transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) because these two growth factors are present in both the pulmonary milieu of those at risk for lung cancer as well as in the tumor microenvironment. EGF significantly enhanced TGF-beta1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-beta1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGF receptor (EGFR) inhibition, neutralizing antibody against amphiregulin, or mitogen-activated protein kinase kinase (MEK) inhibition blocked TGF-beta1-mediated COX-2 induction. COX-2 induction by TGF-beta1 depended upon Smad3 signaling and required the activity of EGFR or its downstream mediators. Autocrine amphiregulin signaling maintains EGFR in a constitutively active state in HBECs, allowing for COX-2 induction by TGF-beta1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-beta1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-beta1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.

In order to examine how tumorigenicity is abrogated by gap junctional intercellular communication (GJIC), protein expression was analyzed in four related mouse lung epithelial cell lines that vary in their GJIC status and neoplastic potential. Since alterations in protein expression underlie neoplastic behavior, this proteomic analysis provides insights into the molecular pathogenesis of lung cancer. E10, an immortalized but non-tumorigenic cell line derived from alveolar type II pneumocytes, has functional GJIC. E9, a spontaneous transformant of E10, is GJIC-deficient and is tumorigenic upon injection into a syngeneic mouse. Stable transfection of E9 with Gja1, the gene for the gap junctional protein, connexin 43, re-established GJIC and rendered this line (designated E9-2) non-tumorigenic; the vector transfection control line, E9-41, remains tumorigenic. Proteins extracted from these cell lines were separated by two-dimensional electrophoresis (2DE) and visualized by Coomassie blue staining. We consistently observed differential expression of 27 proteins between E10 and E9 and identified 11 of these by peptide mass mapping. The functions of these proteins include stress response, cytoskeletal structure, signal transduction, apoptosis, immune response, pre-mRNA processing, and carbohydrate metabolism. Gja1 transfection affected the concentrations of four of these proteins, viz. PDI, alpha-enolase, aldolase A, and gelsolin-like protein. PDI concentration was most profoundly affected; E10 cells contain twice as much PDI as E9, and PDI was restored to E10-like levels in the E9-2 transfectant line while remaining at E9-like levels in the vector control E9-41 cells. An association between connexin 43 and PDI expression was also observed in a second set of independently derived type II cell lines. The PDI superfamily has multiple cellular roles including chaperoning assembled glycoproteins, regulating the activities of transcription factors, and regulating disulfide bond formation.