The Role of TBI-Derived DAMPs in Bacterial Pneumonia
Abstract
Pneumonia (PNA) is common after all major injuries but is especially common after traumatic brain injury (TBI), where 30-60% of patients who require mechanical breathing support will develop a significant PNA. The high frequency of PNA after TBI was historically thought to be related to mechanical factors like loss of protective swallowing reflexes with bacterial aspiration into the airway. Clearly, bacteria are needed to initiate infection, but our previous PRMRP work clearly shows that the presence of bacteria in the airway is not enough to cause PNA. Rather, when PNA develops, it reflects an altered balance of forces between the patient’s immune system and bacteria that are always present, but cause infection more readily when the immune system is compromised. Also, using antibiotics to tip the balance toward clearing bacteria is of limited value since the bacteria become resistant to antibiotics so rapidly. PNA is also well known to prolong the critical illness phase of TBI, increasing ICU and hospital stay and thus contributing to poor outcomes in head-injured Warfighters. What is less well known but has come into focus more recently, is that infection also directly worsens neurologic recovery from brain injury both in the short and the long term. This places huge burdens on the military medical care system as well as on the medical care and social support systems in place to supply chronic care for wounded Warfighters. Thus, new approaches to controlling infection in wounded soldiers are clearly needed, and therapies that can prevent the establishment of PNA without resorting to antibiotics are especially important. Critically, therefore, we have now shown that major injuries directly cause immune suppression, and that it is this immune suppression and dysfunction that makes injured Soldiers so susceptible to bacterial infection. Injury-related immune suppression occurs in great measure because injured tissues themselves release molecules into the circulation that alter immunity. These molecules are called danger signals or DAMPs. Our research over the last 5 years has not only allowed us to identify those molecules in detail, but has also allowed us to determine how circulating DAMPs make normal immune cells less responsive to bacteria. We and others have now shown that traumatic brain injuries release the same kinds of DAMPs other injuries do. In other exciting advances, we have now found that the DAMPs released by injury have specific effects on immune cells function that can lower their ability to kill bacteria. We have now described these effects in detail, and have shown that we can reverse them. And, in fact, we have now identified several well-known drugs that can reverse the effects of injury on PNA. We have clearly demonstrated the success of that approach in test-tube cellular models as well as in mouse and pig models of systemic injuries that release DAMPs. Thus with the recent discovery that DAMPs are released by TBI, study of these approaches in head trauma models is clearly indicated. Based on our novel understanding of immune responses to injury, we show two commonly used, safe, non-toxic drugs can be re-purposed to reverse immune suppression caused by TBI. These are 1) the anti-depressant paroxetine (PAR / Paxil) and 2) the seizure medication valproate (VAL/Depakote). Both are generic drugs with long histories of clinical use and excellent safety profiles. In addition, 3) we have found that heme (a red blood cell breakdown product) is also a key DAMP. Heme is normally cleared from plasma by the protein hemopexin (HPX), but HPX is exhausted by trauma. This allows free heme to increase PNA risk. Heme is rapidly metabolized however, in the presence of very safe, low concentrations of carbon monoxide (CO). CO causes the body to produce heme oxygenase-1, a protective molecule that breaks heme down to prevent it from causing more harm to cells and tissues. We now show
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311052
Entities
People
- Leo E Otterbein
Organizations
- Beth Israel Deaconess Medical Center
- United States Army