Leukocytes and mediators in bronchoalveolar lavage during allergen-induced late-phase asthmatic reactions

We have measured the total and differential cell counts, histamine, leukotriene (LT) B4 and LTC4, immunoglobulins, complement (C3), eosinophil-derived basic proteins, and monocyte complement rosettes in bronchoalveolar lavage (BAL) 6 h after challenge with either antigen or diluent control in seven patients with antigen-induced single early reactions, and seven with dual (early and late phase) reactions. In both groups, the total cell counts in BAL were similar, irrespective of whether they were challenged with antigen or diluent. However, in the late-phase responders (LPR), there were significant increases in lymphocytes, neutrophils, and eosinophils (p less than 0.05), and significant decreases in the percentage of lung mast cells (p less than 0.05). The eosinophil major basic protein and eosinophil-derived neurotoxin increased in four of five subjects with dual responses and in the majority of single early responders (SER). BAL histamine concentrations increased in five of seven patients with dual responses. There were no consistent changes in LTB4 concentrations in either the LPR or the SER between diluent and antigen days, but a small but significant increase in LTC4 was observed in the LPR. Concentrations of IgG, IgA, IgM, IgE, C3, and albumin did not differ significantly. The percentage of monocyte complement rosettes also increased significantly (p less than 0.05) in LPR, but not in SER. These findings support the hypothesis that eosinophils and their products play a role in tissue injury in LPR and that eosinophil infiltration may be associated with macrophage activation.     

Leukocytes as Modulators of Stellate Cell Activation

Activation of stellate cells is central to the process of hepatic fibrogenesis. Stellate cell activation can be influenced by many factors, including cytokines, oxidants, and alterations in the perisinusoidal extracellular matrix. These factors can be produced by resident liver cells (hepatocytes, Kupffer cells, or stellate cells themselves); however, infiltrating leukocytes may also play an important role. Because liver fibrosis often follows a prolonged period of hepatic inflammation, investigators have begun to study leukocytes as modulators of stellate cell activation. The following data summarize recent investigations in this area that focus on neutrophils as well as mononuclear cells.     

Patient-controlled analgesia for severe cancer pain

Concern with the suboptimal management of pain in hospitalized patients has led to the development of a patient-controlled analgesia system. In this system, a preset amount of narcotic is delivered intravenously when the patient activates the demand button. We tested the safety and efficacy of this mode of treatment in eight patients with cancer suffering from severe pain. Respiratory rates, mental status, and pain relief were recorded at baseline and during the study period. Morphine sulfate doses ranged from 1 to 5 mg, and lockout intervals from 15 to 90 minutes. Patients had a higher analgesic demand, ie, self-administered more doses, during the first four hours than during the remaining time of treatment. Respiratory rates decreased during the first four hours of treatment, but no cases of significant respiratory depression were encountered during this period or thereafter in the study. Significant pain relief was produced in all patients without causing undue sedation. Patient acceptance of this mode of therapy was excellent, and the majority of patients preferred this type of analgesia to other forms of pain treatment. In conclusion, patient-controlled analgesic is effective and safe therapy for cancer pain.     

Emergency department analgesia for fracture pain

STUDY OBJECTIVES: We analyze records of all emergency department (ED) patients with extremity or clavicular fractures to describe analgesic use, compare analgesia between adults and children, and compare analgesia between the subset of these adults and children with documented moderate or severe pain. Among children, we compare treatment between pediatric and nonpediatric facilities. METHODS: Analysis of the ED component of the National Center for Health Statistics National Hospital Ambulatory Medical Care Survey for 1997 through 2000 was conducted. The proportion of patients with closed extremity and clavicular fracture that received any analgesic and narcotic analgesic medications was determined for each age category. Survey-adjusted regression analyses compared pain and narcotic medications by age and ED type (pediatric versus other). Analyses were repeated for the subset of patients with moderate or severe pain severity scores. RESULTS: Of 2,828 patients with isolated closed fractures of the extremities or clavicle, 64% received any analgesic and 42% received a narcotic analgesic. Pain severity scores were recorded for 59% of visits overall, 47% of children younger than 4 years, and 34% of children younger than 1 year. Among patients with documented moderate or severe pain, 73% received an analgesic and 54% received a narcotic analgesic. Compared with adults, a lower proportion of children (< or = 15 years) received either any analgesic or a narcotic analgesic (P <.001). After adjustment for confounders and survey design, the proportion of patients aged 0 to 3, 4 to 8, 9 to 15, 16 to 29, 30 to 69, and 70 years and older who received any analgesic was 54% (95% confidence interval [CI] 41% to 67%), 63% (95% CI 57% to 68%), 60% (95% CI 57% to 64%), 67% (95% CI 62% to 73%), 68% (95% CI 64% to 72%), and 58% (95% CI 52% to 65%), respectively; the proportion who received a narcotic analgesic was 21% (95% CI 11% to 31%), 30% (95% CI 22% to 37%), 27% (95% CI 23% to 32%), 47% (95% CI 40% to 54%), 51% (95% CI 46% to 56%), and 41% (95% CI 35% to 48%), respectively. Compared with children treated in other EDs, children treated in pediatric EDs were about as likely to receive any analgesia (adjusted relative risk [RR] 1.1; 95% CI 0.9 to 1.3) or narcotic analgesia (adjusted RR 0.9; 95% CI 0.6 to 1.2). CONCLUSION: In pediatric and adult patients, pain medications were frequently not part of ED treatment for fractures, even for visits with documented moderate or severe pain. Pain severity scores were often not recorded. Pediatric patients were least likely to receive analgesics, especially narcotics.     

Chemokines as mediators of neovascularization

Chemokines are a superfamily of homologous heparin-binding proteins, first described for their role in recruiting leukocytes to sites of inflammation. Chemokines have since been recognized as key factors mediating both physiological and pathological neovascularization in such diverse clinical settings as malignancy, wound repair, chronic fibroproliferative disorders, myocardial ischemia, and atherosclerosis. Members of the CXC chemokine family, structurally defined as containing the ELR amino acid motif, are potent inducers of angiogenesis, whereas another subset of the CXC chemokines inhibits angiogenesis. In addition, CCL2, a CC chemokine ligand, has been implicated in arteriogenesis. In this article, we review the current literature on the role of chemokines as mediators of neovascularization.     

Leukotrienes as mediators of asthma

This review describes the aspects of leukotriene (LT) pharmacology and biology that are relevant to their important role in asthma. The biosynthesis and metabolism, including transcellular metabolism, of LTB4 and the cysteinyl-LTs (i.e. LTC4, LTD4 and LTE4) are described, and their transport is briefly outlined. The existence, distribution and pharmacological characterization of the receptors (BLT, CysLT1, CysLT2), as well as the transduction mechanisms triggered, are discussed in detail. We also describe their effects on airway smooth muscle tone, hyperresponsiveness and proliferation, on vascular tone and permeability, on mucus secretion, on neural fibers and inflammatory cell functions. Finally, the evidence supporting their role as asthma mediators is reviewed, including the effects of anti LT drugs (both biosynthesis inhibitors and receptor antagonists) in experimental and clinical asthma.     

Role of pain in placebo analgesia.

The hypothesis that perceived pain intensity can influence placebo analgesia was tested. One hundred and seven subjects rated their pain from from 0 to 10 on a visual analog scale after a standard wisdom tooth extraction. The expected course of such postoperative pain in the absence of therapy or placebo is a steady increase; this was confirmed by blind administration of the placebo. When placebos were given intravenously in view of the patients, some (placebo nonresponders) reported that their pain increased, whereas others (placebo responders) reported that their pain either decreased or remained the same over the next 60 min. A placebo response was more likely to occur if the pain rating 5 min prior to placebo administration (initial pain) was greater than 2.6. Furthermore, placebo responders with initial pain above this 2.6 level reported significantly greater mean analgesia than those with lower initial pain. Indeed, responders with initial pain less than 2.6 reported no change in pain during the 60 min after administration of a placebo. When their initial pain level was greater than 2.6, they reported a steady decline in pain over this period. However, above the 2.6 level there was no obvious relationship between the magnitude of the placebo analgesia and the initial pain.     

Cytokines as mediators of graft-versus-host disease

Cytokines are proteins produced mainly by lymphocytes in response to an antigenic stimulus. Originally identified and named on the basis of their biological activity, they are now called interleukins; together with the interferons, colony-stimulating factors and tumour necrosis factor/cachectin (TNF) they form a complex and overlapping network of communication between immunocompetent cells. Cytokines play a central role in T cell activation, and interleukin 2 and interferon gamma in particular are involved in the expression of graft-versus-host disease after bone marrow transplantation. Recent studies suggest that TNF is also implicated: the gene encoding TNF is situated close to the MHC gene in both mice and humans, and TNF is able to up-regulate constitutively expressed class II antigen and, with interferon gamma, to induce class II expression in previously normal cells. Bacterial lipopolysaccharide (endotoxin) is a powerful stimulus to TNF, and TNF production may be the mechanism underlying the longstanding observations on the role of the bacterial microflora of the gut in graft-versus-host disease.     

Endogenous opioids as mediators of asthma

Changes in airway innervation are believed to play a key role in the pathophysiology of asthma. A group of regulatory peptides which act as neuroregulators is resembled by the opioids. Their localization to neurons projecting into airways suggested a possible role as regulators of neurogenic inflammation, bronchoconstriction and mucus secretion. They mainly act through modification of tachykinergic and cholinergic impulses and their ability to inhibit bronchoconstriction prompted discussion of their potential value in asthma therapy. Apart from the presence of the classical opioids and their receptors in the lung and their functional role, a new group of peptides such as nociceptin and endomorphins have been characterized in the airways. Whereas at least endomorphin-1 acts via the classical OP(3) (mu) receptor, nociceptin binds to a new receptor termed opioid receptor-like-receptor (ORL(1)) and inhibits tachykinergic constriction. Contrary to these promising modulatory effects on airway smooth muscle tone, effective therapeutic strategies have not been developed yet. In conclusion, opioids resemble a group of regulatory peptides which are present within airway-innervating nerve fibres and influence a multitude of airway functions via modification of neural transmission.     

Microparticles as mediators and biomarkers of rheumatic disease

Microparticles (MPs) are small membrane-bound vesicles that arise from activated and dying cells and enter the blood to display pro-inflammatory and pro-thrombotic activities. MPs are 0.1-1.0 μm in size and incorporate nuclear, cytoplasmic and membrane molecules as they detach from cells. This process can occur with cell activation as well as cell death, with particles likely corresponding to blebs that form on the cell surface during apoptosis. To measure particle expression, flow cytometry allows determination of particle numbers based on size as well as surface markers that denote the cell of origin; platelet MPs are usually the most abundant type in blood. As shown in in vitro and in vivo systems, MPs can promote inflammation and thrombosis resulting from their content of cytokines like IL-1 and pro-coagulant molecules like tissue factor. Certain particle types can be anti-inflammatory, however, suggesting a range of immunomodulatory activities depending on the cell of origin. Studies on patients with a wide range of rheumatic disease show increased MP numbers in blood, with platelet and endothelial particles associated with vascular manifestations; increased numbers of particles also occur in the joint fluid where they may drive cytokine production and activate synoviocytes. In autoimmune diseases such as SLE and RA, MPs may also contribute to disease pathogenesis by the formation of immune complexes. MPs thus represent novel subcellular structures that can impact on the pathogenesis of rheumatic disease and serve as biomarkers of underlying cellular disturbances.     

Blood coagulation factors as inflammatory mediators

After the first observations about blood coagulation by Hippocrates, it took until the early 1900s before the classic theory of blood coagulation was presented. As more and more other coagulation factors were discovered, the four-factor coagulation scheme became more complex, but better understood, leading to the current coagulation cascade. As during the last decade it turned out that coagulation factors might do more than just promoting (or inhibiting) blood coagulation, new scientific avenues were pursued focusing on coagulation-independent properties of individual coagulation factors. This led to the current understanding that coagulation factors, like tissue factor (TF), FVII, FX, and thrombin, are important players in inflammation, vascular development, angiogenesis, and tumorigenesis. However, the molecular mechanism by which coagulation factors exert their pleiotropic effects in pathophysiology remains one of the major challenges in the field. This overview presents current insight in how the main coagulation factors might induce inflammation.