Project title:

Reducing inflammation to improve burn injury repair

Chief Investigator:

Professor Allison Cowin

Funding Amount:

$65,000

Recipient:

University of South Australia

Overview:

Burns are one of the most common injuries in young children. They cause lifelong scarring and frequently contract as the child gets older, requiring extensive surgical intervention to prevent deformity and contracture. Inflammation is a fundamental component of wound healing, however, excessive inflammation is detrimental and leads to fibrosis and scarring. Therapies currently exist to dampen inflammation in other diseases. Since inflammation plays such a significant role in fibrosis and scarring the use of these existing therapies could rapidly lead to new therapeutic approaches for burns.

Research outcomes:

Researchers:

Allison Cowin, Rachael Murray

Research Completed:

2016

Research Findings:

Burns are one of the most common injuries that occur in young children. They can cause lifelong scarring and frequently contract as the child gets older, requiring extensive surgical intervention to prevent deformity and loss of movement. The aim of our project was to improve the healing of burn wounds by developing a new therapy that would prevent the excessive inflammatory response caused by burn injury that leads to fibrosis and scar formation. Our studies identified integrin al as a central regulator of the migration of monocyte inflammatory cells from the blood and into the wound. Therefore, al antibodies were used to dampen the inflammatory response after the initial burst of beneficial inflammation. When tested using wound models we observed an initial delay in healing following al treatment, however, by day 28 the overall area of the resulting scar was reduced, with the scars more closely resembling unwounded skin than their control counterparts. Treatment with the anti-al antibody improved the remodelling of collagen in the burned area and led to improved wound resolution and reduced scarring and fibrosis. The results are promising and further studies are required to fully validate the effectiveness of this therapy for the treatment of burns.

Key Outcomes:

Burns are one of the most common injuries that occur in young children. They can cause lifelong scarring and frequently contract as the child gets older, requiring extensive surgical intervention to prevent deformity and loss of movement. Inflammation is a fundamental component of wound healing; however, excessive inflammation is detrimental and leads to fibrosis and scarring. The aim of our project was therefore to improve the healing of burn wounds by developing a new antibody therapy that would dampen inflammation to improve the healing process and help reduce the development of scar tissue.

The agent that was to be delivered to the burn wounds was a neutralising antibody to lntegrin alpha l(anti­ al). Our studies identified the surface integrin alpha l (al), as a central regulator of the migration of monocyte inflammatory cells from the blood and into the wound. We also showed that al is immune specific, being highly expressed on burn patient monocytes, making it an ideal candidate for targeted anti-integrin therapy for burn wounds. In burn injuries some inflammation is beneficial, and indeed neutrophils are important in preventing wound infection, so timing of the anti-integrin approach was critical for the success of new wound therapy. We therefore evaluated the effectiveness of reducing monocytes entering wounds after the initial influx of neutrophils by targeting monocyte infiltration at day 1, thus allowing some inflammation to occur but at a greatly reduced level.

An in vivo wound trial was performed using Balb/C mice with partial thickness scald burn injuries (n=8), delivering 50µg anti-al or lgG control via tail vein injection, 24 hours post burn injury. We found anti-al antibodies reduce inflammation in burn wounds with a significant reduction in the number of macrophages within the wound (26.5 cells/2.Sx106 µm2 anti-al versus 122 cells/2.5×106 µm2 lgG control) by 7 days burn injury. Treatment of mouse scald burns with an anti-al antibody led to a slower rate of healing at day 3 with 35.3% wound closure with anti-al treatment compared to 49.3% closure in lgG control mice, in line with previous studies on macrophage depletion in incisional wound healing. However, by day 28 the overall area of the resulting scar was reduced and spectrophotometric analysis showed that scarring was improved with less redness observed. Histological examination of the burns revealed the neo-epidermis was thinner than controls, similar to that observed in unwounded skin and the cross sectional area of the dermal scar was reduced. Overall collagen deposition was improved in the anti-al treatment group at day 28 with the scars more closely resembling unwounded skin than their control counterparts. Treatment with the anti-al antibody reduced the Collagen I/Ill ratio (3.79 lgG vs 3.08 anti-al) which is indicative of a reduction in scarring and fibrosis. These studies suggest that a targeted integrin al therapy reduces macrophage infiltration into burn wounds leading to reduced scar formation following burn injury. Further studies are required to determine if this short-term application of function-blocking integrin alters the ability to fight infection in burn wounds. However, the results are a promising step forward in the development of an anti-inflammatory therapy for the treatment of burn wounds.

In summary we are developing a new therapy for burn wound treatment using the short-term delivery of specific function-blocking integrin antibodies which improve healing and reduce scar formation in a mouse burn model. The results are promising with an improvement in the appearance of the scar being observed but further studies are required to fully validate the effectiveness of this antibody therapy for the treatment of burn injuries.

Research Papers:

Publication in Preparation:

Strudwick  X L,  Murray  RZ,  Cowin AJ . Development  of  an  integrin  al antibody  therapy  for  reducing inflammation  and scarring  in burn wound  injuries  Manuscript  in Preparation.

Conference Presentation:

Strudwick X L, Murray RZ, Cowin AJ . Development  of an integrin al antibody therapy for  reducing inflammation  and scarring in burn wound  injuries Australasian  Wound & Tissue  Repair Society Conference,  Melbourne, 2016; Nov 7-9

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