Calcium entry inhibition during resuscitation from shock attenuates inflammatory lung injury

Cindy Lee, Da Zhong Xu, Eleonora Feketeova, Zoltan Nemeth, Kolenkode B. Kannan, György Haskó, Edwin A. Deitch, Carl J. Hauser

Research output: Article

17 Citations (Scopus)

Abstract

Trauma and hemorrhagic shock (T/HS) induce a systemic inflammatory response syndrome (SIRS). Neutrophils (polymorphonuclear leukocytes [PMN]) and other cells involved in acute lung injury (ALI) are activated by Ca 2+ entry. Thus, inhibiting Ca 2+ entry might attenuate post-traumatic lung injury. Inhibiting voltage-operated (1-type) Ca 2+ channels during shock could cause cardiovascular collapse, but PMN are "nonexcitable" cells, lack L-type channels, and mobilize Ca 2+ via nonspecific channels. We previously showed that PMN Ca 2+ entry requires sphingosine 1-phosphate synthesis by sphingosine kinase and that both sphingosine kinase inhibition and blockade of nonspecific channels attenuate ALI when begun before shock. Pretreatment for clinical injuries, however, is impractical. Therefore, we now studied whether Ca 2+ entry inhibition that begun during resuscitation from T/HS could attenuate SIRS and ALI without causing hemodynamic compromise. Male Sprague-Dawley rats underwent laparotomy and fixed-pressure shock (mean arterial pressure, 35 ± 5 mmHg; 90 min). Sphingosine kinase inhibition or nonspecific Ca 2+ channel inhibition was begun after resuscitation with 10% of shed blood. We then studied in vivo PMN activation and associated lung injury in the presence or absence of Ca 2+ entry inhibition. Neither treatment worsened shock. Each treatment decreased CD11b expression, respiratory burst, PMN p38 MAP-kinase phosphorylation, PMN sequestration, and lung capillary leak in vivo The similar results seen with two different forms of inhibition strengthen the conclusion that the biological effects seen were specific for calcium entry inhibition. Ca 2+ entry inhibition is a candidate therapy for management of lung injury after shock.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalShock
Volume30
Issue number1
DOIs
Publication statusPublished - júl. 1 2008

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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    Lee, C., Xu, D. Z., Feketeova, E., Nemeth, Z., Kannan, K. B., Haskó, G., Deitch, E. A., & Hauser, C. J. (2008). Calcium entry inhibition during resuscitation from shock attenuates inflammatory lung injury. Shock, 30(1), 29-35. https://doi.org/10.1097/SHK.0b013e318145a589