Articles of note…
Imatinib mesylate therapy for lung fibrosis
Lung fibrosis occurs in numerous disease processes, including the chronic remodeling associated with asthma. Recent insight suggests that the related pathogenesis might involve dysregulated cytokine signaling in fibroblasts. In this article, the authors demonstrate that the Abelson tyrosine kinase (Abl) signals downstream from TGF in fibroblasts. Notably, inhibition of Abl with imatinib mesylate (Gleevec) prevented TGF-induced signaling, including collagen gene expression. In addition, using a mouse model of bleomycin-induced pulmonary fibrosis, the investigators demonstrate significant inhibition of lung fibrosis with imatinib mesylate. These exciting results draw attention to the potential utility of targeted therapy against tyrosine kinases for the treatment of lung fibrosis, including asthma.
(Daniels et al. J Clin Invest 2004;114:1308-16.)
Chronic corticosteroid therapy predisposes to cardiovascular disease
The potential adverse effects of chronic corticosteroid therapy include obesity, hypertension, and hyperglycemia, each of which might predispose to cardiovascular (CV) disease. This epidemiologic study in Scotland investigated 68,781 chronic corticosteroid users and 82,202 nonusers without previous hospitalization for cardiovascular disease. The subsequent incidence of CV events was 17 per 1000 patient-years in the nonusers. The incidence of CV events was not significantly increased in those using only inhaled, nasal, or topical corticosteroids or in those receiving <7.5 mg prednisolone per day. However, the incidence of CV events in those receiving ≥7.5 mg prednisolone per day was 77 per 1000 patient-years, leading to a 2.6-fold increased risk for such CV events. These findings suggest that chronic use of at least 7.5 mg prednisolone per day (doses sometimes needed in severe asthma) is associated with a significantly increased risk for CV disease. The fact that such chronic corticosteroid therapy in the patients studied was for a variety of disorders points to a corticosteroid effect rather than that of a particular underlying disease predisposing to CV events.
(Wei et al. Ann Intern Med 2004;141:764-70.)
Adverse effects of chronic albuterol treatment related to the type of receptor
Previous studies have suggested that the overall adverse effects on asthma outcomes seen in some patients treated chronically with inhaled albuterol (Alb) might be related to particular polymorphisms (Arg/Arg at position 16) in the β-adrenergic receptors. This masked, crossover study compared regular use of inhaled Alb versus placebo over a 16-week period in a group of individuals with mild asthma who were either Arg/Arg (n = 37) or Glyc/Glyc (n = 41) genotype in the β-adrenergic receptor. After this time, Alb inhalation increased the peak flow rate more than did placebo inhalation in the Gly/Gly asthmatic individuals. The opposite situation, with less response to Alb than to placebo, was seen in the Arg/Arg individuals. This pattern of different responses to Alb in Glyc/Glyc and Arg/Arg patients was also seen in assessments of FEV1, symptom scores, and use of supplemental reliever medication. These findings might explain why adverse asthma outcomes are seen in only some asthmatic individuals who inhale Alb chronically on a regular basis.
(Israel et al. Lancet 2004;364:1505-12.)
The SARS epidemic in 2003
The epidemic of severe acute respiratory syndrome (SARS) in southeast Asia in 2003 caused major concerns around the world because of the high rates of severe morbidity and mortality involved and the threat to other populations, particularly those with underlying cardiopulmonary disease, including individuals with asthma. This report summarizes the clinical characteristics of the SARS epidemic in Hong Kong in 2003. Approximately 50% of those with the syndrome were apparently infected in clinics, hospitals, or eldercare/nursing homes, 23% of all cases being seen in health care workers. There was a short incubation period (mean, 4.6 days) and rapid progression from symptom onset to hospitalization in the more severe cases (2-8 days). In fatal cases, the mean time from symptom onset to death was 23.7 days, with increased patient age and comorbid conditions as risk factors for fatal outcomes. Hopefully, the identification of the pathogen as an unusual coronavirus will permit development of protective measures.
(Leung et al. Ann Intern Med 2004;141:662-73.)
HLA-B is the dominant HLA determinant of HIV immunity
HLA class I molecules have a high rate of polymorphism, implicating them in adaptive immunity against viral infections. However, the relative contributions of HLA-A and HLA-B alleles have not been evaluated. In the present study, the investigators examined class I–restricted CD8 T-cell responses against the human immunodeficiency virus (HIV-1). Notably, they found a significantly greater number of HLA-B–restricted responses in a large African patient cohort. Particular HLA-B variants, but not HLA-A variants, were associated with distinct disease characteristics, including CD4 T-cell counts. These data, combined with observations that B alleles evolve more rapidly than A alleles, indicate that HLA-B is the dominant HLA locus influencing immune responses to HIV and subsequent disease outcome. These findings have implications for HIV research and vaccine development.
(Kiepiela et al. Nature 2004:432:769-74.)
Lysosomal glycosphingolipid identified as natural endogenous NKT cell ligand
NKT cells are a distinct lineage of T cells that predominantly participate in innate responses, inasmuch as they express a relatively conserved T-cell receptor (TCR). Although the TCR of NKT cells has been shown to be autoreactive to the lipid-presenting molecule CD1 and reactive to numerous microbial lipids, the endogenous ligand(s) for these cells has not been identified. In this study, using mice deficient in the lysosomal enzyme beta-hexosaminidase b, the investigators identify a lysosomal glycosphingolipid of previously unknown function, isoglobotrihexosylceramide (iGb3), as the ligand of NKT cells in mice and human beings. Furthermore, they show that chemically synthesized iGb3 is able to directly stimulate NKT cells to produce TH1 and TH2 cytokines. Finally, using a lectin that specifically binds to iGb3 (and inactivates it), the investigators block NKT cell stimulation and autoreactivity in vitro. In addition to uncovering basic properties of NKT cells, this article offers new hope for manipulating NKT cells with new iGb3-based pharmaceutical agents.
(Zhou et al. Science 2004;306:1786-9.)
Mast cell angiopoietin 1 promotes plasma cell tumors
Mast cells are frequently associated with tumors, but their role has been controversial. In the case of multiple myeloma, elevated levels of mast cells are associated with disease severity. In order to elucidate the mechanism of this effect, the investigators first demonstrate that mast cells specifically synthesize the pro-angiogenic factor angiopoietin 1 (Ang-1). Through use of an in vivo angiogenesis assay, coinjection of mast cells with plasma cells is shown to promote blood vessel and tumor cell growth (compared with injection of plasma cells alone). Furthermore, neutralization of Ang-1 (with a soluble receptor antagonist) is shown to block these parameters, especially when done in conjunction with blockade of vascular endothelial growth factor. These results demonstrate that inflammation stimulates tumor cell growth by accelerating angiogenesis, providing compelling evidence that blockade of mast cell associated inflammation might have a role in the management of specific malignancies.
(Nakayama et al. J Clin Invest 2004;114:1317-25.)
Other articles of interest
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Hayashi et al. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 2004;114:270-9.
Epidemiologic evidence suggests an inverse relationship between microbial exposures in early childhood and the subsequent prevalence of allergic asthma in such individuals living in developed countries. If such a relationship is proven, the underlying mechanisms are not clear. In this study, it was found that ligands for Toll-like receptor type 9 (TLR9) induce high levels of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism in various organs. TLR9 ligand–induced pulmonary IDO activity inhibits TH2-driven experimental asthma. IDO activity expressed by resident lung cells rather than by pulmonary dendritic cells suppressed lung inflammation and airway hyperreactivity. Thus, the findings in this study suggest a mechanism by which an innate immune response to microbial components could suppress TH2-mediated allergic responses.
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Campos et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2004;170:947-51.
Disturbed sleep is common in asthma. Melatonin is used extensively by healthy individuals as an aid to help sleep, but its effects in asthmatic individuals is not well defined. This controlled study in 22 female adults with asthma (8 of whom were “poor sleepers”) showed that melatonin, 3 mg, taken 2 hours before bedtime, significantly helped the quality of sleep, with shorter onset and longer duration of sleep (P = .04). There was no effect of melatonin administration on asthma symptoms or peak flow measurements.