Trauma-Induced Acute Lung Injury (TIALI)

Acute lung injury is a serious complication of major trauma occurring as a direct consequence of trauma to the lung or, more commonly, arising indirectly as a consequence of trauma elsewhere to the body. Trauma-induced acute lung injury (TIALI) significantly contributes to severe respiratory failure and the development of the high mortality disorder (30-40% mortality) known as “acute respiratory distress syndrome” or ARDS.   A spectrum of severity exists, however acute respiratory distress syndrome (ARDS) is defined as the most severe form of injury. The frequency of ARDS with severe trauma is unclear but is believed to occur in approximately 15- 25% of cases, and is also associated with burn and head injuries.  ARDS causes a huge social and financial impact, with many survivors requiring a prolonged critical care stay and a significant number having a poor quality of life a year after the injury.

TIALI Causes

TIALI and ARDS are particularly vexing challenges in military casualties who survive combat trauma including blast explosions, hemorrhagic shock (with massive blood transfusion), burns and smoke inhalation injury. Over a third of burned battlefield causalities ultimately develop ARDS and the number of military personnel exposed to blast-induced trauma has greatly increased in recent military conflicts and terrorist attacks accounting for >70% of combat casualties in Iraq and Afghanistan. TIALI can also be caused by blunt force trauma in motor vehicle accidents or other incidents which induce major blunt force trauma.

Insights

Sadly, insights into TIALI and ARDS pathobiologies have been incremental. A key advance, however, has been appreciation of the key contribution of activated evolutionarily-conserved systemic inflammatory networks to the development of multiple organ dysfunction in critically ill patients with sepsis, trauma, and ARDS. All forms of trauma (blast explosions, hemorrhagic shock, smoke inhalation) potently activate inflammatory cascades releasing multiple inflammatory cytokines (“cytokine storm”) that increase vascular permeability resulting in organ edema, multi-organ dysfunction, and a dismal prognosis. Another key advance to understanding ARDS pathobiology, has been the observation that mechanical stress generated by mechanical ventilation, required by many TIALI subjects and virtually all ARDS patients, also potently activates inflammatory cascades, and contributes to increased TIALI/ARDS mortality, i.e. ventilator–induced lung injury (VILI). Mechanical ventilation is life-saving in critically ill patients experiencing respiratory failure, however, the development of VILI extends the duration of ventilatory support  and significantly contributes to TIALI and ARDS mortality. VILI also occur in mechanically ventilated patients without ARDS.

Current care of critically ill domestic and military personnel with trauma or ARDS remains largely supportive and completely fails to address the profoundly destructive influence of unchecked inflammation on driving TIALI, ARDS, or VILI outcomes. Unfortunately, unlike oncology and cardiology where breakthrough drugs have emerged (PD-1 inhibitors, Herceptin, statins etc.), every drug in the ICU is generic and novel therapeutic interventions in TIALI and ARDS are completely absent as result of the failure of many clinical trials across various ARDS clinical trial networks world-wide. Thus, a serious unmet need in the critically ill and in military trauma casualties is to identify effective therapies that reduce the mortality of TIALI.

ALT-100 Benefits

We have successfully developed pre-clinical models of hemorrhagic shock-, blast-, pneumonia- and mechanical ventilation-induced lung injury that produce robust “inflammatory cytokine storm”, and increased multi-organ edema and dysfunction. Utilizing these preclinical models, and genomic-intensive strategies, we identified nicotinamide phosphoribosyl transferase (NAMPT) as a novel ARDS plasma biomarker, and novel therapeutic target to address the development and severity of TIALI, ARDS and VILI. We showed that secreted NAMPT, i.e. extracellular eNAMPT, functions as a highly inflammatory, master regulatory cytokine in the circulation via binding of Toll-like receptor 4 (TLR4), thereby potently inducing NFκB-mediated lung and systemic inflammation. We have shown that eNAMPT is a damage-associated molecular pattern protein (DAMP) expressed by multiple species in response to potentially injurious danger signals including shock, sepsis, trauma and excessive mechanical stress, and is directly linked to VILI development and ARDS mortality. eNAMPT neutralization via anti-eNAMPT polyclonal (pAb) or murine monoclonal antibodies (mAbs), strongly support this premise reducing TIALI, ARDS and VILI in our preclinical models. ALT-100 is a humanized mAb that neutralizes circulating eNAMPT, as an effective therapy in military casualties with trauma and in the critically ill. Targeting eNAMPT, an upstream NFκB-activating cytokine, has the capacity to directly dampen inflammatory amplification loops, and reduce the severity of TIALI, ARDS and VILI. We propose to administer ALT-100 to soldiers in the field at risk for developing TIALI. In addition, we propose to as well as to administer ALT-100 to individuals in the ER or entering the ICU at the time of intubation prior to exposure to mechanical ventilation. These highly innovative preventive strategies directly addresses the unmet need for novel therapies for TIALI, ARDS, or VILI.