Lorena Airaghi

α-Melanocyte-stimulating Hormone in Normal Human Physiology and Disease States

Abstract Over the past two decades, research in animal models has indicated that α-melanocyte-stimulating hormone (α-MSH) has potent anti-inflammatory properties. Furthermore, recent data show that the peptide has antimicrobial effects and probably contributes to innate immunity. α-MSH, which is produced by many extrapituitary human cells, should no longer be considered solely a pituitary hormone; rather, it should be viewed as a ubiquitous modulatory peptide.

Endogenous cytokine antagonists during myocardial ischemia and thrombolytic therapy

We tested the idea that cytokine antagonists are released during acute myocardial ischemia to counteract proinflammatory effects of cytokines. We investigated changes in plasma concentrations of the anticytokine molecules alpha-melanocyte-stimulating hormone (alpha-MSH), interleukin-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor (sTNFr) in patients with acute myocardial infarction (AMI) or unstable angina (UA). Blood samples were collected at presentation in the coronary care unit, at 3-hour intervals for 24 hours, and daily for 4 days thereafter. There were no significant differences in the concentrations of cytokine antagonists in patients with AMI or UA. However, whereas concentrations of alpha-MSH were increased in early samples of patients with AMI or UA who were treated with a thrombolytic agent, they were consistently low in untreated patients. IL-1ra concentrations likewise were greater 3 and 6 hours after treatment in patients who underwent thrombolysis, whereas there was no significant difference in plasma sTNFr between the two groups. We suggest that during myocardial ischemia and thrombolysis anticytokine molecules released from the injured myocardium become available to reduce inflammation caused by cytokines and other mediators of inflammation.

α‐MSH in Systemic Inflammation: Central and Peripheral Actions

ABSTRACT: Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on α‐melanocyte stimulating hormone (α‐MSH). Increases in circulating TNF‐α and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of α‐MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central α‐MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central α‐MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central α‐MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by α‐MSH could be used to treat systemic inflammation. In addition to its central influences, α‐MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. α‐MSH reduces chemotaxis of human neutrophils and production of TNF‐α, neopterin, and NO by monocytes. In research on septic patients, α‐MSH inhibited release of TNF‐α, interleukin‐1β (IL‐1β), and interleukin‐8 (IL‐8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.

The Neuropeptide α-MSH in Host Defense

Abstract: The presence of the ancient peptide a‐melanocyte‐stimulating hormone (α‐MSH) in barrier organs such as gut and skin suggests that this potent anti‐inflammatory molecule may be a component of the innate host defense. In tests of antimicrobial activities, α‐MSH and its fragment KPV showed inhibitory influences against the gram‐positive bacterium Staphylococcus aureus and the yeast Candida albicans. Anti‐tumor necrosis factor and antimicrobial effects of a‐MSH suggest that the peptide might likewise reduce replication of human immunodeficiency virus (HIV). Treatment with α‐MSH reduced HIV replication in chronically and acutely infected human monocytes. At the molecular level, α‐MSH inhibited activation of the transcription factor NF‐κB known to enhance HIV expression. α‐MSH that combines antipyretic, anti‐inflammatory, and antimicrobial effects could be useful in the treatment of disorders in which infection and inflammation coexist.

Cytokine antagonists in infectious and inflammatory disorders.

Knowledge of the precise events involved in responses to inflammatory or infectious stimuli in man and lower animals is still incomplete. However, certain cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are believed to be involved in these resp0nses.l The potent effects of these and other cytokines, if not modulated by endogenous actions, would likely lead to dire consequences for the host. Therefore, it is not unreasonable to expect that actions of cytokines are normally modulated by other endogenous soluble mediators. Cytokine antagonists modulate cytokine actions, and a balance between the production of cytokines and cytokine antagonists apparently is important to control host responses. We investigated changes in plasma concentrations of three cytokine antagonists, a-melanocyte-stimulating hormone, interleukin1 receptor antagonist, and soluble tumor necrosis factor receptor, in infectious and inflammatory disorders and the relationship of these antagonists with disease activity.

Neuropsychological functions and metabolic aspects in subclinical hypothyroidism: the effects of L-thyroxine.

Thyroid hypofunction is a slowly progressing graded phenomenon [Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43(1):55-68]; subclinical forms (SCH) often represent a laboratory diagnosis in apparently asymptomatic patients. In the absence of adequate parameters for thyroid hormone action in tissues, the level of TSH increase corresponding to negative effects remains unsettled. We studied a wide range of physiological processes in a strictly selected population of 38 female patients (56.4+/-12.6 years) with minor forms of SCH (TSH 6.6+/-1.8 mIU/L), after exclusion of neurological, psychiatric and somatic disorders or confounding conditions. The investigations, performed at admission and after 6 months of l-thyroxine (LT4) treatment, included metabolic evaluation, health status perception and an extensive battery of neuropsychological tests and psychological rating scales. Lipid metabolism improved after LT4 (total cholesterol: 231.9+/-49.6 mg/dl pre- vs 221.0+/-40.0 mg/dl post-treatment; LDL cholesterol: 183.1+/-62.9 vs 162.7+/-53.7 mg/dl; apolipoprotein A1: 183.5+/-64.5 vs 160.9+/-50.3 mg/dl; p<0.05 for all comparisons), while glucose metabolism was unchanged. Health status perception was favourably influenced by the treatment (total SF-36 score 97.8+/-18.4 pre- vs 108.5+/-14.8 post-, p<0.0001); in a matched control group with euthyroid goiter, tested to examine the effects of medical care in the absence of treatment, no significant differences were found in the SF-36 scores at admission and after 6 months (109.3+/-15.1 vs 109+/-14.2, p=0.9). Attention performance improved after LT4; HRSD and HRSA scores did not significantly change, but negative correlations were found between FT3 levels and affective scores at admission, and between the post-treatment changes of affective scores and of FT3. In our study subtle disturbances of health status perception, attention and lipid metabolism associated to SCH of mildest degrees were reverted by LT4 replacement, reinforcing reports of unfavourable consequences of marginal thyroid disease.

Hormonal response during antigenic challenge in normal subjects.

In recent years, it has been demonstrated that neuroendocrine and immune systems are functionally correlated. In particular, hypothalamic-pituitary-adrenal axis may be activated by a cytokine, interleukin- 1 which stimulates corticotropin releasing hormone (Sapolsky, Rivier, Yamamoto, Plotsky & Vale, 1987) and eventually determines an increase in corticosteroids which, in turn, inhibit interleukin- 1 production (Besedovsky, Del Rey, Sorkin & Dinarello, 1986). This immune-endocrine feedback loop may be a relevant mechanism of control of the immune response and it has been suggested that an impairment of this circuit may be involved in certain autoimmune disease (Schauenstein, Fassler, Dietrich, Schwarz, Kromer & Wick, 1987). Information about endocrine-immune connections in human subjects derived from in vivo studies is very scanty. A report by Meyer, Smith, Richards, Cavallo, Morril, and Blalock (1 987) investigating cortisol response to typhoid antigen in hypopituitary children, demonstrated that immunization elicits a significant increase in cortisol secretion in normal subjects and no response in hypopituitary children. The aim of this paper was to investigate the adrenal response to antigenic challenge in normal adult subjects. 15 normal subjects, 9 men and 6 women, aged 23-52yr were included in this study. All had received a primary immunization series. After giving informed consent, each subject received either 0.5 ml of saline or tetanic toxoid (Anatetall, Sclavo) intramuscularly at 09:OO hr in two nonconsecutive days. Blood samples were collected from an indwelling heparinized catheter at 0, 1, 2, 4, 6, 8, and 10hr after injection. Plasma specimens were analyzed by radioimmunoassay techniques for ACTH, prolactin (PRL), growth hormone (GH), and cortisol levels using commercially available kits. Results were assessed for statistical significance by means of the paired t test. During control test, cortisol levels decreased regularly in serial sampling. After antigenic challenge, cortisol concentrations at 4 and 6 hr were significantly higher than those observed at the same intervals of the control test (mean f SEM; 12.50pg/ dl +_ 0.87 vs 9.37 +_ 0.66 at 4hr; p = .01; and 9.73 k .62 vs 7.77 +_ .55 at 6hr, p = .02, respectively)(Figure 1). At baseline, plasma ACTH, GH and PRL levels were in normal range and showed minor fluctuations following either saline or tetanic toxoid injection in all subjects. Our data demonstrated that an antigenic stimulation determined a significant rise

Cushing’s Syndrome due to Unilateral Adrenal Nodular Hyperplasia with Incomplete Inhibition of the Contralateral Gland

A 57-year-old woman was demonstrated to be affected by adrenocorticotropic hormone (ACTH)-independent Cushings syndrome. Computed-axial tomography of the abdomen demonstrated an expansion of the left adrenal. In apparent contrast with these findings, adrenal scintigraphy demonstrated radiocholesterol uptake also by the right gland. At surgery, the left adrenal was found to be hard and enlarged and was excised, while the right gland was found of normal appearance and left in place. Histologic examination of the excised gland demonstrated nodular hyperplasia. Early after surgery, plasma cortisol returned to normal values with a normal circadian rhythm and complete inhibition by low dose dexamethasone; the response of plasma cortisol to ACTH was normal. The patient represents a rare case of unilateral adrenal nodular hyperplasia. Radiocholesterol uptake by the contralateral gland and early recovery from adrenal atrophy after surgery are exceptional findings and suggest incomplete inhibition of endogenous ACTH.

Prevalence of late-onset adrenal hyperplasia in postmenarchal hirsutism.

The response of plasma 17-hydroxyprogesterone (17-OHP) to exogenous ACTH was investigated in 85 consecutive women referred for postmenarchal hirsutism, in order to assess the prevalence of late-onset adrenal hyperplasia due to 21 -hydroxylase deficiency and its relevance to the clinical practice. An exaggerated response of plasma 17-OHP to ACTH, indicating 21-hydroxylase deficiency, was found in only one patient with a prevalence of 1.1 %. The patient with late-onset adrenal hyperplasia presented signs of virilism and had high basal levels of 17-OHP. On the basis of our results, late-onset adrenal hyperplasia accounts for a very small proportion of cases of hirsutism; moreover, from this and previous studies it is apparent that the determination of basal plasma 17-OHP may be sufficient to discover late-onset 21-hydroxylase deficiency. Therefore, we do not consider ACTH testing an advisable step in the routine screening for hirsutism.

Thalassemic osteopathy: A new marker of bone deposition

Osteopathy represents a prominent cause of morbidity in patients with beta-thalassemia major (TM) and manifests as osteopenia/osteoporosis. Biochemical turnover markers (BTMs) are considered a useful, non-invasive tool for the clinical follow-up of osteoporotic patients; they can provide a dynamic view of the remodeling process and give information on the metabolic activity of bone tissue as well as on the pathogenesis of bone loss. The amino-terminal pro-peptide of type I procollagen (P1NP) is a recently introduced marker that is considered the most sensitive index of bone formation. Although demonstrated in several categories of patients with bone disease, there is little information on the clinical usefulness of this bone formation index in thalassemic patients. We evaluated the P1NP levels of 53 adult patients with b-thalassemia major (21 males and 32 females, mean age 34.5 ± 5.7, range 22-46 years) and associated osteopathy. We investigated the correlation between P1NP and bone condition as examined by dual X-ray photon absorptiometry and with BTMs expressing bone resorption and bone mineralization (carboxyterminal collagen cross-linked (CTX) terminal regions of type I collagen and osteocalcin, respectively). P1NP serum levels were correlated with CTX levels (r=0.545, p<0.001); the results were unchanged when males and females, as well as osteoporotic and osteopenic subgroups, were considered separately. No correlation was demonstrated neither between OC and CTX (r=0.17, p=ns), nor between P1NP and OC levels (r=0.11, p=ns). No correlation was demonstrated among the P1NP/CTX ratio and age, OC or densitometric values and no difference was found in the same ratio between osteopenic (0.19 ± 0.16) and osteoporotic (0.15 ± 0.14) patients. Similar results were obtained for the OC/CTX ratio, as it was not correlated with age, P1NP or densitometric values. This is the first report of circulating P1NP in patients with TM-associated osteoporosis. P1NP and CTX assays show good precision and low analytical CV, and, compared to other markers, they can acceptably reflect bone metabolic processes and promptly respond to antiosteoporotic treatments. We trust that this sensitive marker can be useful in the assessment of treatment efficacy and can overcome the pitfalls due to wide variability in the normal values of most BTMs that create difficulty in pinpointing the individual patients response.