Calcium entry inhibition during resuscitation from shock attenuates inflammatory lung injury.
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 Ca2+ entry. Thus, inhibiting Ca2+ entry might attenuate post-traumatic lung injury. Inhibiting voltage-operated (L-type) Ca2+ channels during shock could cause cardiovascular collapse, but PMN are "nonexcitable" cells, lack L-type channels, and mobilize Ca2+ via nonspecific channels. We previously showed that PMN Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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. Ca2+ entry inhibition is a candidate therapy for management of lung injury after shock.
Lee
Cindy
C
Department of Surgery, Division of Trauma, New Jersey Medical School, Newark, New Jersey, USA.
Xu
Da-Zhong
DZ
Feketeova
Eleonora
E
Nemeth
Zoltan
Z
Kannan
Kolenkode B
KB
Haskó
György
G
Deitch
Edwin A
EA
Hauser
Carl J
CJ
D000627:Aminophenols / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D039481:CD11b Antigen / Q000187:drug effects; D002118:Calcium / Q000097:blood; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D009568:Nitrendipine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011014:Pneumonia / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016897:Respiratory Burst / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000188:drug therapy*; D012774:Shock, Traumatic / Q000188:drug therapy*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
D000627:Aminophenols; D039481:CD11b Antigen; D002118:Calcium; D002121:Calcium Channel Blockers; D009568:Nitrendipine; D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C503978:MRS 1845