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LETTERS TO THE EDITOR

Reply to Eisenhut

Laboratory of Basic Science, Nephrology Department, University of São Paulo School of Medicine, São Paulo, Brazil

REPLY: Leptospirosis is a zoonotic disease of global importance and can be caused by any one of more than 11 species and 200 serovars of spirochetes of the genus Leptospira (2). In recent years, a severe form of leptospirosis, involving pulmonary hemorrhage, has emerged as a serious clinical syndrome (8, 9). The mechanisms of pathogenesis, host defense, and protective immunity remain poorly understood. Understanding the mechanisms of immunity to leptospirosis is of major importance in developing a successful vaccine against leptospirosis as well as in gaining insight into the pathogenesis of natural or induced infection.

In an article recently published in AJP-Renal Physiology, we investigated epithelial sodium transporter protein expression in an animal model of leptospirosis with the objective of determining the mechanisms involved in the pathogenesis of pulmonary edema in this condition (1). We found that, in pulmonary cells, expression of epithelial sodium channel protein was reduced, and NKCC1 protein expression was increased. In his Letter to the Editor regarding that same article, Eisenhut (6) hypothesized that the most likely mechanism explaining these changes in epithelial membrane ion transporter protein expression is the effect of the cytokines tumor necrosis factor (TNF) and interleukin (IL)-1. This is a plausible explanation, given that Eisenhut et al. (4, 5) have shown that, in other models of infectious disease, including meningococcemia, such a mechanism is involved. The authors showed that, in meningococcal septicemia patients with pulmonary edema, levels of TNF and IL-1 are high, and systemic epithelial ion transport is impaired, leading to greater fractional excretion of sodium, as well as to elevated levels of sodium in sweat and saliva.

In a kinetic study, Vernel-Pauillac and Merien (10) compared the mRNA expression levels of various cytokines in the peripheral blood mononuclear cells of Leptospira interrogans-inoculated hamsters. The authors observed pronounced mRNA expression of the Th1 cytokines TNF-, interferon- (IFN-), and IL-12, with transcripts being detected as early as 1 h postinfection. In addition, the expression of anti-inflammatory cytokines, such as IL-4 and IL-10, was prominent from 1 to 4 days postinfection in response to infection with L. interrogans. It has also been demonstrated that levels of soluble IL-2R, IL-6, TNF-, IFN-, and IL-12 are elevated in sera obtained from patients treated for acute leptospirosis (3, 7).

Eisenhut (6) has raised a very interesting point that merits further consideration and investigation.

FOOTNOTES

Address for reprint requests and other correspondence: A. C. Seguro, Laboratório de Pesquisa Básica LIM-12, Faculdade de Medicina da USP, Av. Dr. Arnaldo 455, sala 3310, CEP 01246-903, São Paulo, Brazil (e-mail: trulu{at}usp.br)

REFERENCES

1. Andrade L, Rodrigues AC, Sanches TRC, Souza RB, Seguro AC. Leptospirosis leads to dysregulation of sodium transporters in the kidney and lung. Am J Physiol Renal Physiol 292: F586–F592, 2007.[Abstract/Free Full Text]
2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, Levett PN, Gilman RH, Willig MR, Gotuzzo E, Vinetz JM. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis 3: 757–771, 2003.[CrossRef][ISI][Medline]
3. de Fost M, Hartskeerl RA, Groenendijik MR, Poll TV. Interleukin 12 in part regulates -interferon release in human whole blood stimulated with Leptospira interrogans. Clin Diagn Lab Immunol 10: 332, 2003.[CrossRef]
4. Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Pediatr Crit Care Med 7: 119–124, 2006.[CrossRef][ISI][Medline]
5. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (Lond) 3: 5, 2006.[CrossRef][Medline]
6. Eisenhut M. Cytokine effects on epithelial ion transport protein expression in leptospirosis. Am J Physiol Renal Physiol; doi:10.1152/ajprenal.00110.2007.
7. Petros S, Engelmann L. Serum procalcitonin and proinflammatory cytokines in a patient with acute severe leptospirosis. Scand J Infect Dis 32: 104, 2000.[CrossRef][ISI][Medline]
8. Segura ER, Ganoza CA, Campos K, Ricaldi JN, Torres S, Silva H, Cespedes MJ, Matthias MA, Swancutt MA, Lopez Linan R, Gotuzzo E, Guerra H, Gilman RH, Vinetz JM. Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden. Clin Infect Dis 40: 343–351, 2005.[CrossRef][ISI][Medline]
9. Silva JJ, Dalston MO, Carvalho JE, Setubal S, Oliveira JM, Pereira MM. Clinicopathological and immunohistochemical features of the severe pulmonary form of leptospirosis. Rev Soc Bras Med Trop 35: 395–399, 2002.[Medline]
10. Vernel-Pauillac F, Merien F. Proinflammatory and immunomodulatory cytokine mRNA time course profiles in hamsters infected with a virulent variant of Leptospira interrogans. Infect Immun 74: 4172–4179, 2006.[Abstract/Free Full Text]

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