ARDS is a severe, often life-threatening of several systemic disorders and direct injury to the lungs. It is major component of multiple organ dysfunction syndrome (MODS) and a manifestation of the systemic inflammatory response syndrome (SIRS) that can develop in trauma patients.
Causes:
ARDS can be precipitated by various serious medical and surgical conditions such as pneumonia, aspiration of gastric contents, sepsis, severe trauma with shock, and multiple transfusions.
Symptoms:
ARDS is a syndrome of acute pulmonary inflammation and resultant increased capillary endothelial permeability. ARDS of different aetiologies is characterized by local inflammatory response. The formation of fibrin-rich exudates (hyaline membranes) in the lumen of lung alveoli is a morphological hallmark of ARDS.
Mechanisms to Pathology:
Intra-alveolar fibrin deposition occurring as a result of damage to the capillary endothelium or the alveolar epithelium significantly contributes to the pathologenesis of ARDS by decreasing surfactant activity, whic
h favors alveolar collapse, and by decreasing alveolar fluid clearance.
Tissue Factor upregulation:
Tissue Factor (TF) is a 47 kDa transmembrane glycoprotein which enalbes cells to initiate the coagulation cascade. The extracellular N-terminal domain of TF contains functional sites for factor VIIa (FVIIa) binding (e.g., Lys20). The coagulation cascade is triggered when TF binds to FVIIa.
An etiologic role for TF in spesis indued respiratory and fenal falure have been demonstrated and blockage of TF effectively preserves both pulmonary and renal function (Ezban (US2004/0033200A1).
Broncoalveolar lavage fluid (BALF) from ARDS pateints have been shown to have procoagulant activity that is tissue factor dependent and is more profound during the first 3 days following the clinical diagnosis of ARDS. TF which initiates coagulation in vivo is present only in minimal amount in the circulating blood under physiological conditions. However, several inflammatory mediators, including complement anaphylatoxins and cytokines, up-regulate TF expression in circulating leukocytes and thereby increase the thrombogenic activity of the blood. The inflammatory mediators also spill over into the general circulation. Lambris (US12/669695)
Complement upregulation: In vitro, C5a and the terminal complex of complement, C5b-9 induce tissue factdor expression on endothelial cells and monocytes, and assembly of C5b-9 on the surface of platelets has been shown to stimulate prothombinase activity. Goldenberg (US2006/0140936A1) disclose improved therapeutics for treating sepsis by providing multispecific antagonists that target two or more of coagulation factors, proinflammatory cytokines and complement activation products. In one embodoment, Goldenberg teaches a multispecific antagonist to TF and to a complement factors, specially C3, C5, C3a, or C5a and thrombin.
Treatment:
Complement and Cytokine inhibitors:
–Inhibition of C3 and C3b: Bansal (US2008/023313A1) teaches methods of inhibiting C3b dependent complement activation by limiting C3 cleavage as with an anti-C3 antibody as being useful for the treatment of a pulmonary condition such as acute respiratory distress syndrome.
Lambris (US12/669695) discloses a method for treating acute respiratory distress syndrome (ARDS) by administering a complement inhibitor inhibitor such as compstatin. Similarly, Lambris in WO 99/13899 teaches complement inhibiting compounds such as compstatin which are useful in treating disorders such as ARDS.
Francois (US2010/0166862A1) teaches a method of treating a complement mediated disorder by adminsitering a complement inhibitor such as an inhibitor of C3 which can be a compstatin analog. Among the numerous complement disorders listed by Francois is adult respiratory distress syndrome.
–Inhibition of C5a binding to C5aR: Lambris (US12/669695) teaches that inhibition of C5a binding to C5aR is effective to reduce tissue factor expression in nuetrophils present in alveolar fluid of ARDS patients which in turn reduces the pro-coagulant activity of aveolar fluid. A number of C5aR inhibitor are known in the art. C5a activity may be inhibited by pventing formation of C5a as by inhibiting the cleavage of C5 by C5-convertase. Eculizumab, for example, is an anti-C5 anitobdy that binds to C5 and prevents its cleavge into C5a and C5b. Formation of C5a may also be inhibited indirectly by inhibting the clevage of C3 which yields C3b and C3a. A C3 inhibitor such as compstatin, for example, can be used to inhibit C3.
Hagen (J. of Surgical Research 46, 195-199 (1989) also showed that anti-human C5 antibodies resulted in attenuation of septic shock and pulmonary edema in a ARDS primate model.
Maxwell (US2006/0217530A10 discloses cyclic petidic and peptidomimetic antagnosts of C5a receptors which are are useful in the treatment of a variety of inflammatory conditions such as ARDS.
Inhibition of TNF-alpha:Lambris (US12/669695) discloses that inhibition of TNF lapha is effective to reduce or prevent tissue factor expression in nuetrophils present in alveolar fluid of ARDS pateints which in turen reduces the pro-coagulant activity of aveolar fluid. TNF alpha inhibitors include antibodies such as adalimumab and infliximab.
Inhibition of Tissue Factor (TF)
Uttehnthal (US8,088,728B2) discloses methods of treating lung diseease such as ARDS and fibrin deposition in the airways such as the alveolar or bronchoalveolar spaces by administering human tissue factor pathway inhibitor (TFPI)
Complement Regulatory Proteins
CR1: Levin (US6,169,068B1) teaches treatment of a lung disease such as adult respiratory distress syndrome (ARDS) by administering a soluble complement receptor type 1 (sCR1).